Anophthalmia and microphthalmia in children: associated ocular, somatic and genetic morbidities and quality of life

ABSTRACT

Purpose

To report ocular outcome, somatic co-morbidities, genetics, and quality of life in children born with anophthalmia (A) or microphthalmia (M).

Methods

Thirty-five children (19 boys) with A/M underwent ophthalmological examinations and a review of medical records. Parents of 12/22 cases completed the Pediatric Quality of Life Inventory (PedsQL).

Results

Age at examination ranged from 7 months to 18 years (median 2.3 years). Ten cases were totally blind or had light perception. Isolated A/M occurred in 16/35 cases, while somatic, psychomotor, neuroradiological and/or genetic pathology occurred in 19/35 cases both in the bilateral (7/9) and in the unilateral group (12/26). Among 26 unilateral cases, 4/16 with one normal eye had associated problems compared to 9/10 if the contralateral eye was pathological (p < .01). There was an increased risk for heart defects in children with psychomotor delay (p = .04). Pathogenic genetic abnormalities were identified in 10/24 cases. Neuroimaging demonstrated pathology in 14/20 cases with corpus callosum dysgenesis (6/20) being the most common. The median total PedsQL score of parent reports for ages 2–12 was 52.4 (range 22.6–100).

Conclusions

Somatic, psychomotor and/or neuroradiological pathologies were more common in bila-teral than unilateral cases, but the difference was not significant. There was decreased risk in unilateral cases with one normal eye. Genetic defects occurred in both unilateral and bilateral cases. Health-related quality of life was reduced.

KEYWORDS:

• Anophthalmia
• microphthalmia
• genetic evaluation
• blindness
• somatic examination
• quality of life

Introduction

Clinical anophthalmia (A) is described as the complete absence of the eye globe in the orbit with no ocular structure seen during macroscopic clinical examination. Microphthalmia (M) is defined as an underdeveloped eye, either only a small rudiment or an eyeball of subnormal size, more explicitly a bulb with a total axial length that is at least <2 standard deviations (SD) below the mean for age. The combined prevalence of A and M has been reported to be 0.4–3.2/10, 000 live births (1–7). A/M can occur in isolation, together with other ocular malformations or somatic co-morbidities or as part of a syndrome and demonstrate extensive clinical and genetic complexity and heterogeneity (1).

A/M account for 11% of blind children worldwide (1) and are among the top five causes of severe visual impairment in Sweden (8). The potential for vision is dependent on whether the case is uni- or bilateral, the size of the bulb and/or-associated ocular or cerebral pathology. The most common ocular malformation associated with A/M is “coloboma” which is-an ocular fissure closure defect (OFCD) in the same and/or in the contralateral eye (9). In A/M, there is also a risk of deficient orbital growth with subsequent evolvement of facial asymmetry (9,10).

A/M may be caused by-numerical chromosomal abnormalities like trisomy 18 (11) or trisomy 13 (12) as well as by variants in many single genes, including PAX6, SOX2, OTX2 and CHD7 (13,14).

The mutations can be de novo or inherited. In severe bilateral cases of A/M, a genetic cause has now been identified in approximately 80% of cases, with de novo heterozygous loss-of-function mutations in SOX2 or OTX2 being the most common (15).

In addition to optimising visual outcome, early oculoplastic treatment with socket expansion using-“conformers” is important for eyes with an axial length of <16 mm. The goal is simultaneous expansion of the eyelids, soft tissue and the orbital bones in order to minimise facial asymmetry and to facilitate wearing a prosthesis (16). To promote visual function, clear rather than opaque conformers are fitted-in cases with light perception or positive visual evoked potential (VEP).

The purpose of the study was to evaluate and compare visual outcome, ocular pathology, somatic associated morbidities and genetic causative factors in children born with unilateral or bilateral A/M. Further aims were to evaluate their health-related quality of life (HRQoL)

Material and methods

St. Erik Eye Hospital’s database was searched for patients <18 years of age with the diagnoses of congenital A/M, ICD10 numbers Q11.1 and Q 11.2. After excluding patients who had been treated surgically for congenital cataract, 46 patients with A/M were identified. In total 35 patients eligible for inclusion agreed to participate in this cross-sectional cohort study with prospective longitudinal follow-up and were assessed at our departments of Paediatric Ophthalmology and Oculoplastic and Orbital services between 2018 and April 2021. One patient reached the age of 18 before assessment-but was still included. Eligible cases were followed up 9–27 months after the first notification.

The clinical ophthalmological examinations included, where possible, best corrected visual acuity (BCVA) with acuity cards (Teller acuity cards, Precision Vision, Illinois, USA) or-optotypes (LEA-Test Ltd, Helsinki, Finland or Konstantin Motakis Ortho KM, Lund, Sweden), microscopy and fundus evaluation. Facial photography and scrutiny of ophthalmological, paediatric and genetic medical records were performed.

The ocular diagnosis of A or M was based on a clinical evaluation, which showed a non-existent eye or a small eye with coexisting microcornea. The total axial length was measured using magnetic resonance imaging (MRI), computed tomography (CT) scans or ocular ultrasound in 21/35 cases and was defined as the length from the cornea to the central area of the retina. Microphthalmia was confirmed if the axial length was <2 SD below mean for age. Testing with visual evoked potential (VEP) had been performed or was initiated in cases where the visual potential was unclear.

The patients born with A/M were categorised according to four different subgroups using a modified version of Skalicky (17) and Groot (18). 1) M with a smaller but otherwise normal bulb, or an ocular remnant or anophthalmia (ORA), 2) M with OFCD, 3) M with anterior segment dysgenesis (ASDG) or persistent foetal vitreous (PFV) or 4) M with combined defects in the anterior or posterior segment (COMB). When the A/M was bilateral, it was classified according to pathology leading to visual impairment in the best eye.

The paediatric resident evaluated information from medical records regarding family history, pregnancy, labour, and somatic associated morbidities such as heart defects, psychomotor delay and abnormal cerebral findings on MRI. The genetic testing was performed as part of clinical analysis and comprised of microarray testing, investigation with A/M gene panels and/or whole exome or genome sequencing. The results from clinical genetic testing were collected and reviewed by the clinical genetic resident.

A logistic regression analysis was performed including age, gender, bilaterality and subgroups as predictors for estimating the associated risk of heart defects, other severe somatic comorbidities, psychomotor delay, genetic pathology, and abnormalities found using-neuroradiological scanning.

The Pediatric Quality of Life Inventory (PedsQL), a validated tool that covers physical, emotional, social and school functioning, was used for measuring HRQoL. Self-reports (children aged 5–18 years) and parent reports (children aged 2–12 years) were used in the current study. The scores were calculated according to instructions from the developers (19).

The study was performed according to the Helsinki Declaration, with ethical approval from the local committee. Informed consent was obtained from the parents/guardians and from adolescents above the age of 15.

Results

Demographics and presentation

Among the 35 cases, unilateral A/M occurred in 26/35 (74%) and bilateral in 9/35 (26%). There were 19 boys (54%) and age at examination ranged from 7 months to 18 years (median 2.3 years). Three children were prematurely born, nine were delivered by emergency or elective caesarean section, three children had consanguineous parents, and two children were born after in vitro fertilisation. Maternal age ranged from 21 to 48 years (median 32 years).

The majority of cases, 28/35, presented during the first week of life. In 19 children, the parents noticed something odd about the eye or eyes in the first days after birth. Two children, including one with congenital toxoplasmosis, were diagnosed prenatally on ultrasound (Table 1).

Table 1. Demographic data on children with microphthalmia and anophthalmia including age at examination, completed gestational age and birth weight, mode of delivery, diagnosis, unilaterality or bilaterality and microphthalmia subgroup

Case, sex (♀, ♂), age	Gestational age, birth weight, mode of delivery	Diagnosis right eye, left eye	Unilaterally /Bilaterally	Subgroup
1. ♀ 16 m	38 w, 2700 g, ElCS	Microcornea, IODFC RE M and cyst LE	U	OFCD
2. ♂ 2 m	38 w, 3200 g, EmCS	M cyst, lid coloboma LE	U	OFCD
3. ♂ 16 m	41 w, 4400 g, VD	Optic nerve aplasia, microcornea RE M, cataract, amotio LE	U	COMB
4. ♂ 12 m	40 w, 4500 g, EmCS	M, PFV RE	U	PFV
5. ♂ 13 m	42 w, 4100 g, VD	M LE Microcorneae ODFC RELE	U	OFCD
6. ♀ 11 m	40 w, 3500 g, VD	M RELE	U	ORA
7. ♀ 1.8y	33 w, 2400 g, EmCS	M LE Chorioretinal scars RE	U	COMB
8. ♀ 8 m	40 w, 4300 g, VD	M LE	U	ORA
9. ♂ 2.3y	34 w, 2800 g, EmCS	M RE A LE	B	ORA
10. ♀ 6.3y	38 w, 3300 g, VD	A RELE	B	ORA
11. ♀ 1.6y	38 w, 3300, ElCS	M LE ODFC LE	U	OFCD
12. ♂ 8y	40 w, 3500 g, EmCS	M, iridoretinal-coloboma RELE	B	OFCD
13. ♂ 8y	42 w, induction VD	M LE	U	ORA
14. ♂ 1y	39 w, 3700 g, NI	A RE	U	ORA
15. ♂ 5y	39 w, 3100 g, VD	M RELE	B	ORA
16. ♂ 5.8y	Normal, 3500 g, VD	Microcornea, opticnerve aplasia, retinal pigm RE M LE	U	COMB
17. ♀ 5.5y	40 w, 3900 g, EmCS	M, microcornea, yellow opacity LE	U	PFV
18. ♂ 18y	40 w, 3100 g, VD	M, Peters anomaly LE	U	ASDG
19. ♀ 3y	39 w, 4000 g, VD	A RELE	B	ORA
20. ♂ 14 m	40 w, 3800 g, VD	Microcornea, ODFC RE M, microcornea, ODFC LE	U	OFCD
21. ♀ 6.9y	38 w, 3400 g, VD	M, microcornea, ODFC LE	U	OFCD
22. ♂ 8y	40 + 3 w, 3660 g, VD	A RE, foveal hypoplasia LE	U	ORA
23. ♂ 9 m	39 w, 4000 g, VD	M, Peters anomaly RE	U	ASDG
24. ♂ 2.5y	40 w, 3300 g, NI	M, cataract, PFV LE	U	PFV
25. ♀ 8.6y	43 w, NI	M, ASD RE	U	ASDG
26. ♀ 10.3y	40 w, 3500 g, VD	M, microcornea, ODFC /lacunes LE	U	OFCD
27. ♂ 3.8y	39 w, 3200 g, CS	A RE, M LE	B	ORA
28. ♂ 16.6y	32 w, 2000 g, VD	M RE, microcornea, ODFC cataract, keratopathy	U	OFCD
29. ♂ 9y	On term, VD	M cataract RE	U	ASDG
30. ♂ 15 m	40 w, 3400 g, VD	M, microcornea, PFV RE	U	PFV
31. ♀ 13y	39 w, 3200 g, VD	Iris-, funduscoloboma RE IODFC LE	U	OFCD
32. ♂ 2.3y	38 w, 3000 g, VD	M RELE	B	ORA
33. ♀ 6 m	39 w, 3700 g, NI	M RELE	B	ORA
34. ♂ 4 m	39 w, 3500 g, VD	A RE, M LE	B	ORA
35. ♀ 9 m	41 w, 3300 g, VD	M RE	U	PFV

♀: female, ♂: male, ASDG: anterior segment dysgenesis, B: Bilaterally, COMB: combined anterior posterior segment, ElCS: elective cesarean section, EmCS: emergency cesarean section, IODFC: irido optic disc fundus coloboma, LE: left eye, M: microphthalmus, m: months, N: normal, NI: no information, ODFC: optic disc fundus coloboma RE: right eye, OFCD: optic fissure closure defect, ORA: ocular remnant, PFV: persistent fetal vascularisation, U: unilaterally, VD: vaginal delivery, w: weeks, y: years

Visual characteristics including visual evoked potential (VEP)

The best-corrected visual acuity (BCVA) ranged from amaurosis to 1.3. Eight cases with bilateral A/M and two cases with unilateral A/M were blind with amaurosis or at best light perception (WHO categories 4 and 5 visual impairment).

VEP, performed in 7/35 cases, demonstrated distinct cortical response in two children (one had total amaurosis and the other only reacted to light). VEP showed low or uncertain responses in four patients.

Bilateral or unilateral disease

The majority of the bilateral cases, 8/9, were from subgroup ORA (Figure 1a–d).

Figure 1. (a–d) Girl born with total blindness (amaurosis) due to right sided anophthalmia and left sided microphthalmia. There was no bulb on the right side and a very small, rudimentary bulb 5 mm on the left side. (a) New-born child, one month of age. (b) Treatment with expanding conformers, here 10 months of age. (c) Six years of age with bilateral prostheses. (d) MRI of the brain and orbits showing anophthalmia right eye and microphthalmia left eye (Published with permission from parents) .

Of the unilateral cases, 9/26 had OFCD, 5/26 had ORA (Figure 2a–d) and 5/26 had PFV. The other eye was normal in 16/26 unilateral cases, 4/16 had associated co-morbidities, while 9/10 with a pathological contralateral eye had associated co-morbidities (p < .01).

Figure 2. (a–c) Child born with small microphthalmic left eye. (a) Two months of age. (b) Treated with expanding conformers-at eight months of age she is wearing a-left eye prosthesis. Right eye normal. (c) Magnetic resonance tomography (T-2 weighted) of the brain and orbits. Note the microphthalmic left eye. (Published with permission from the parents).

Ocular anomalies in contralateral eyes included cases of papillochorioretinal coloboma (4), retinal degeneration or scars (3) and single cases of optic nerve aplasia (1), foveal hypoplasia (1) or nystagmus (1). For examples of prostheses please see Figure 3.

Figure 3. Prostheses from one child with bilateral anophthalmia.

Refraction

Refraction, which could be-measured in 23 cases, was median +2 Dioptres (D) (range +6.5 D—12 D) in the contralateral eyes of unilateral cases. Two patients could not be measured. In the eyes of most of the patients’ (8/9) with bilateral AM, refractions could be not measured apart from a single eye where the refraction was +0.5 D.

ORA subgroup

All eight cases with bilateral ORA were blind according to WHO categories 4 or 5. Case 9 with chromosome 18q-deletion-syndrome had a severe heart defect and CNS malformations, and died during the study period. Case 32 had a de novo chromosome 13q31.3-q34 duplication. A SOX2 mutation was identified in case 10 who had psychomotor delay and a hypoplastic chiasm. In four cases, no genetic abnormalities were identified, and one child is still under investigation.

Among the five unilateral cases with ORA, three children had subnormal visual acuity with severe myopia, retinal degeneration, nystagmus and/or macular hypoplasia in the contralateral eye. The child with macular hypoplasia, case 22, had a micro-syndrome with BCOR-mutation. He had subnormal hearing and speech problems and a second-degree relative with A. He is described in a previous cohort (20). The child with retinal degeneration, case 13, had a chromosome 17p13.1p13.2-deletion, microcephaly, epilepsy, a congenital heart defect and died during the study period. The third child had normal genetic findings but presented with unilateral cleft lip and jaw, intellectual impairment and vertebral anomalies (Tables 2 and 3).

Table 2. Somatic comorbidities in children with anophthalmia and microphthalmia including subgroup, isolated or non-isolated A/M, genetic findings, magnetic resonance imaging of the bulb and CNS, and disorders in different organ systems

Case, subgroup,	Isolated (I) /Non-I	Genetic pathology	Ocular and cerebral neuroradiological findings	Pathology in the nervous, endocrine, or immune systems	Pathology in heart, spine, kidneys or other organs
1. OFCD	Non-I	De novo heterozygous CHD7-mutation (c.5890 C > T, p.Gln1964*); CHARGE syndrome	AL 20/10 mm 1 d Cyst, n opticus malformation LE Thin CC. Small cerebellar hemisphere	HI. Psychomotor delay	PDA. Choanal atresia
2. OFCD	I	Array-CGH N Gene panel N (21 genes)	AL 17/10 mm 4 dLeft bulb small, absence of lens. n opticus normal. Brain N	N	N
3. COMB	Non-I	Array-CGH N Gene panel N (159 genes)	AL 18/12 mm 4 m No nn opticii, chiasma, tractii. Small ant pituitary gland, thin infundibulum, thin CC.	N	N
4. PFV	I	Not perf	Not perf	N	N
5. OFCD	Non-I	De novo mutation WDR37 (c.386 C > G p.Ser 129Cys) Neurooculocardiogenitourinary syndrome.	AL 17/12 mm 1 w M LE Vermis rotated, possible hypoplasia. Wide perivascular spaces	EP. Psychomotor delay	Tetralogy of Fallot. PA. Vertebral anomalies. Duplex kidney. Hydronephrosis
6. ORA	I	Array-CGH N Gene panel N (54 genes)	US brain N	N	N
7. COMB	Non-I	Not perf	AL 20/11 mm 19 mo Calcifications. Obstructive hydrocephalus. Ventriculocisternostomy.	EP. Psychomotor delay. Speech delay	Congenital toxoplasmosis
8. ORA	Non-I	Gene panel N (61 genes)	AL 17/11 mm 8 w MRI brain N		VSD
9. ORA	Non-I	De novo del18q21.1-qter (30 Mb), including TCF4; 18q-deletion syndrome/Pitt-Hopkins syndrome	AL 11 mm/remnant 3 d Microcephaly, corpus callosum agenesis	HI. Psychomotor delay. Perinatal asphyxia. Ad mortem	Transposition of the great arteries. PA. VSD. PDA
10. ORA	Non-I	De novo heterozygous SOX2 mutation (c.-13_43del, p.M1_P44del); MCOPS3	AL No bulb RE/remnant 5 mm LE 3 mo Thin opitc tract right side. Hypoplastic chiasma Deformation hypothalamus.	Psychomotor delay	No
11. OFCD	I	Not perf	Not perf	N	N
12. OFCD	Non-I	De novo heterozygous RARB mutation (c.1193 C > G, p.Ser398*); MCOPS12-syndrome	AL 18/18 mm 3 y Dilated ventricles. CC dysgenesis?	Neuromusc disease. Spastic diplegia. Diaphragmatic paresis. Psychomotor delay. Speech delay.	Cryptorchidism, unilateral.
13. ORA	Non-I	De novo del 17p13.1p13.2,(1,9 Mb).	AL 26/12 mm 4 y Plago- and microcephaly	EP. Hypotonia Intellectual impairment. Ad mortem.	Atrial septal defect. Abnormal renal circulation.
14. ORA	Non-I	Array-CGH N.WGS panel N (987 genes)	US brain N	Intellectual impairment.	Vertebral anomalies (Th10 and Th 9). Unilateral cleft lip and jaw
15. ORA	I	Array-CGH N	Not perf	N	N
16. Comb	Non-I	Paternally inherited heterozygous OTX2-mut (c.263 C > A p.Ser88*) MCOPS5 syndrome	AL 17/9 mm 12 w Optic nerve aplasia RE, micro och optic nerve hypoplasia LE. Hypoplasia of CC and vermis	Psychomotor delay.
17. PFV	I	Not perf	US brain N	N	N
18. ASDG	I	Ni (performed USA)	Scanning abroad according to parents N	N	N
19. ORA	Non-I	Panel N (20 genes)	Absent bulbs 1 w no nn optici, no chiasma Cyst 8 mm frontal horn.	N	Laryngomalacia. Gastrostomia.
20. OFCD	Non-I	De novo heterozygous CHD7-mutation (c.2959 C > T, p.Arg987*); CHARGE syndrome	AL 17/13 mm 5 d Normal	Deaf one ear, HI one ear. Psychomotor delay	Truncus arteriosus. Tracheostomy. Jejunostomy. Thymic aplasia, Submucous cleft palate. VSD.
21. OFCD	I	Not perf	Not perf	N	N
22***. ORA	Non-I	Maternally inherited hemizygous BCOR -mutation (c.254 C > T, p.Pro85Leu); Lenz microphthalmia syndrome	AL Absent/18 mm 2 w High signal caudal from basal ganglia. Unclear pathology.	HI. Psychomotor delay. Speech problems	Atrial septal defect.
23. ASDG	I	Panel N (63 genes)	Not perf	N	N
24. PFV	I	Not perf	Not perf	N	Cryptorchidism, unilateral.
25. ASDG	I	Not perf	Not perf	N	N
26. OFCD	Non-I	Array-CGH N WES N.	AL 23/19 mm 6.5 y M and coloboma LE, thin ON/ chiasma LE, cavum septum pellucidum et Vergae, short CC	ADHD. Autism.	Beta thalassemia. Suspected Aicardi syndrome.
27. ORA	Non-I	Not perf	CT brain. Absent RE,19 mm 4 y ON-chiasmal hypoplasia M LE. Calcifications.	N.	N
28. OFCD	Non-I	WGS trio variants of unclear clinical significance. Pathogenic mutations for Hyper IgD-syndrome	Not perf	Hyper IgD-syndrome. Asthma.	Aortic coarctation. Aortic Valve Insufficiency. Hypospadia.
29. ASDG	I	Not perf	Not perf	N	N
30. PFV	I	Not perf	AL 12/17 mm US 6 w Not perf	N	N
31. OFCD	I	Panel 61 genes normal	Not perf	N	N
32. ORA	Non-I	De novo dup 13q31.3q34 (22.2 Mb)	AL 9/8 mm 8 mo M, inner ear cochlear malformation, perisylvan PMG, Ventricles enlarged Microcephaly	HI. Psychomotor delay.	VUR.
33. ORA	Non-I	Array-CGH N. WGS trio-analysis N (3921 genes)	AL 5/7 mm 2 w ONH bilat Normal otherwise	Hypotonia. Bronchotracheal anomalies. Jejunostomy. Asplenia. Slight psychomotor dealy	Heterotaxy syndrome with left pulmonary hypoplasia, malrotation ventricle and intestines. Cardiac anomaly.
34. ORA	I	Array-CGH N. WGS panel N (72 genes).	Absent RE/12 mm 2 d Not performed US brain N	N	N
35. PFV	I	Array-CGH N.	AL 9/18 mm 2 mo ONH RE MRI brain N	N	N

*** Included in study from Gothenburg.

ADHD: attention deficit hyperactivity disorder, Axial length AL: and Age at MRI/CT/US ASD: atrial septal defect, CC: corpus callosum, COMB: combined anterior posterior segment, d days, EP: epilepsy, HI: hearing impairment, I isolated, IODFC: irido optic disc fundus coloboma, LE: left eye, m: months, MRI: magnetic resonance imaging, N: normal, Non-I non-isolated, Not perf not performed, OFCD: optic fissure closure defect, ORA: ocular remnant, ONH: optic nerve hypoplasia, PA: pulmonary atresia, PDA: patent ductus arteriosus, RE: right eye, RELE: right and left eye, US: ultrasound, VCS: ventriculocisternostomy, VSD: ventricular septal defect, VUR: vesicoureteral reflux, w: week, y: years.

Table 3. Ocular characteristics including diagnosis, visual functions, VEP, intraocular pressure, treatment with expander (E) and/or prosthesis (P)

Case, sex (♀, ♂), age (y, m, w)	Ocular characteristics	BCVA VEP (if performed)	IOP mmHg	Treated with E or P, data from latest follow up
1. ♀ 16 m	Microcornea, IODFC RE M, cyst LE	1.8 c/d RE = 0.066	14/	EP LE 2.2y
2. ♂ 2 m	N RE M, cryptophthalmus LE	Ac 0.1	10/	E LE 2.5y
3. ♂ 16 m	Microcorn optic discaplasia RE M, cataract, amotio LE	Am/Am. VEP: Low amplitudes	9/11	EP LE 2.5y
4. ♂ 12 m	M, microcorn, PFV, cataract RE N LE	L/FF	6/8	No P 2.1y
5. ♂ 13 m	Microcornea, IODFC RE. M,microcorn, cataract IODFC LE	2.4 c/d RE Am or L? LE VEP: Unclear	9/4	Referred for P 2.1y
6. ♀ 11 m	M RE N LE	A/9.8 c/d	/10	EP RE 1.8y
7. ♀ 1.8y	Chorioretinal scars RE M, microcorn,chorretinalscarsLE	F/Am	11/7	P LE 3.0y
8. ♀ 8 m	N RE M LE	F/Am	11/	EP LE 1.8y
9. ♂ 2.3y	M RE A LE, lash ptosis, low eyebrow	Am/Am (Reacts to light!)	np	EP Bilat 2.3y
10. ♀ 6.3y	A RE, lash ptosis M LE	Am/Am VEP: Low LE.	np	EP Bilat 7.5y
11. ♀ 1.6y	N RE M, microcornea, ODC LE	FF/FF VEP: Low LE	10/9	No P 3.5y
12. ♂ 8y	Microcornea, IODFC RE LE	0.03/0.2	np	No P 9.3y
13. ♂ 8y	Retinal pigmentation RE M, microcornea LE	2.4 c/d binoc	18/ni	No EP 8y
14. ♂ 1y	A RE, low, broad eyebrow N LE nystagmus	0.3 c/d	Ni	EP RE 2.3y
15. ♂ 5y	Micro and sclerocornea RE LE	P	Ni	E RELE Clear conf 6.2y
16. ♂ 5.8y	Microcorn retinal pigm/atrophies, optic disc aplasia RE Micro- sclera-cornea, rudimetary lens, ONH LE	Am/P + L VEP: Distinc responses, latency delay	Ni	E LE Clearconf 6.8y
17. ♀ 5.5y	N RE Microcorn, PFV, opacity LE	FF/Am	Ni	EP LE 6.7y
18. ♂ 18y	N RE M, Peters anomaly, LE	1.3/Am	16	P** LE 18y
19. ♀ 3y	A RELE Temporal depression RE	Am/Am	np	EP Bilat 4.2y
20. ♂ 14 m	Microcornea ODFC RE M, microcornea ODFC RE LE	3.6 c/d/1.8 c/d		No EP 2.1y
21. ♀ 6.9y	N RE M, microcornea, ODFC LE	1.0/0.5	Ni	No P 7.8y
22. ♂ 8y	A RE temporal depression RE, low broad eyebrow, lash ptosis, Foveal hypoplasia LE	/0.4	P/14	EP RE 8.9y
23. ♂ 9 m	M, Peters anomaly RE N LE	4.9 c/d = 0.2 LE	14/16	1.5y No P
24. ♂ 2.5y	N RE M, cataract, PFV LE	9.8 c/d = 0.4/Am	10/12	No EP 3.3 y
25. ♀ 8.6y	Irisanomaly, microcornea RE-NLE	Am/1.0	ni	P RE** 9.5y
26. ♀ 10.3y	N RE Microcorneae, ODFC, small lacunes LE	0.5 cc/0.04cc	25/28	Unilat M No EP 11.2y
27. ♂ 3.8y	A RE M LE, Microcorn-iriscolob, cataract	Am/Am	Ni	Referred for EP 4.2y
28. ♂ 16.6y	M, microcornea, keratopathy, cataract, ODFC RE, N LE	Am/1.3	7/15	18y No P
29. ♂ 9y	Microcornea, cataract RE N LE	0.5/0.9	22/18	No P 9.9y
30. ♂ 15 m	Microcornea, PFV, cataract RE N LE	FF	14/13	Referred for P 1.9y
31. ♀ 13.5y	IODFC RE M, microcornea, IODFC LE	0.9/0.06	25/25	No P 13.5y
32. ♂ 2.3y	M Low eyebrows RELE	Am/Am VEP: No answers	NI	Referred for EP 2.8y
33. ♀ 6 m	M RELE	Am/LP VEP: Normal	np	E RELE, Clear conf 1y
34. ♂ 4 m	A RE M LE	Am/A	np	E Bilat 5 m
35. ♀ 9 m	M RE N LE	A/FF and 9,8 c/d	NI	EP RE 7 m

♀: female, ♂: male, M: microphthalmus, A: anophthalmus, Am: amaurosis, E: expander, FF fixates and follows, L: light perception, IODFC: iridooptic disc fundus coloboma, IOP: intraocular pressure, m: months, N: normal, NI: no information, np: not possible, ODC: optic disc fundus coloboma, ONH: optic nerve hypoplasia, P: prosthesis, PL: preferential looking, SE: spherical equivalent, VEP: visual evoked potential, w: weeks, y: years.

** Treatment elsewhere *** Recently arrived in Sweden

OFCD subgroup

In total, 10 children/adolescents had OFCD. None of them were totally blind. Case 12 with bilateral OFCD had a RARB-mutation and MCOPS12-syndrome with neuromuscular disease and psychomotor delay.

Among the nine unilateral cases with OFCD, genetic testing revealed mutations in CHD7 in two children, verifying a clinical diagnosis of CHARGE syndrome and a WDR37 mutation—neurooculocardiogenitourinary syndrome—in one child.

One child showed psychomotor delay, absent corpus callosum and lacunes in the ocular fundus and was suspected to have Aicardi syndrome. Another case had undergone surgery because of aortic coarctation and also had hypospadias. Genetic testing was normal in both children (Tables 2 and 3).

ASDG and PFV subgroups

Four cases had unilateral ASDG and five cases had unilateral PFV. The contralateral eyes had normal visual behaviour for age, but five children were too young to be using symbols. No other birth defects or anomalies were found in the ASDG-group. One child with PFV had unilateral cryptorchidism (Tables 2 and 3).

Combined subgroup

Three children were diagnosed with having combined defects in the anterior as well as the posterior segment. One child had a cataract and retinal detachment with amaurosis in the microphthalmic eye. The other eye was of normal size but amaurotic due to optic nerve aplasia. Genetic evaluation was normal. Case 16 had sclerocornea and a rudimentary lens in the severe microphthalmic left eye and optic nerve aplasia, and retinal atrophy in the amaurotic right eye. Genetic evaluation revealed an OTX2 mutation. The third child had unilateral M due to congenital toxoplasmosis and inactive chorioretinal scars in both eyes (Tables 2 and 3)

Somatic comorbidities, neurodevelopmental disorders and neuroradiological findings

Isolated A/M affecting visual function and craniofacial appearance in otherwise healthy children, occurred in 16/35 cases (46%). A syndromic, non-isolated form of A/M with somatic comorbidities, neurodevelopmental disorders, and/or abnormal neuroradiological findings was found in 19/35 cases (54%), and was more common in 7/9 bilateral than in unilateral cases (12/26) but the difference was not significant.

There was no difference in age between the isolated and non-isolated groups, with median ages of 2.04 (range 0.6–18.0 years) and 2.33 years (range 0.5–16.5 years), respectively.

Echocardiography was performed in 15 patients. Congenital heart defects were present in nine patients and consisted of Tetralogy of Fallot, transposition of the great arteries, truncus arteriosus, aortic coarctation, atrial and ventricular septal defects, aortic valve insufficiency, patent ductus arteriosus and pulmonary atresia. Four patients had undergone cardiac surgery.

Neurodevelopmental disorders were present in 13 cases including psychomotor or speech delay and intellectual disability, but several of the children were too young for proper evaluation during the study period.

Logistic regression analysis showed a significantly increased risk for congenital heart defects in children with delayed psychomotor development when controlled for age, sex, subgroup and ocular diagnosis, with an odds ratio (OR) of 16.8 (p = .04). Furthermore, children with congenital heart defects showed an increased risk of delayed psychomotor development when controlled for age, sex, subgroup, and ocular diagnosis, OR 17.1 (p = .03).

Three patients had epilepsy, five were either deaf or had hearing impairment, one had cerebral palsy and one had both ADHD and autism (Figure 4). Congenital toxoplasmosis was diagnosed in one patient prenatally. A TORCH panel test was checked in three other patients and was found to be negative, whereas four additional patients had negative cytomegalovirus serology tests. MRI or CT of the brain were performed in 19 cases and 1 case, respectively. Pathology was demonstrated in 14/20 with combinations of corpus callosum dysgenesis (6), microcephaly (3), vermis hypoplasia (2), affected pituitary gland (1), aquaeductus stenosis and calcifications (2), ventricular dilation (2) and polymicrogyria (1). Brain ultrasound was performed in four additional cases and were normal in all.

Figure 4. Somatic co-morbidities in patients with anophthalmia or microphthalmia.

Both the patient with the SOX2-mutation and the patient with the OTX2-mutation had hypoplastic chiasmas and the latter also had corpus callosum hypoplasia. Hormonal screening was normal in both patients.

Genetic pathology

Genetic testing according to clinical practice had been performed in 24/35 cases and pathological findings were found in 10/24 (42%). Genetic testing was normal in 14/24 of the tested cases and had not been performed/had not been considered clinically necessary in 10 cases. One child is still under investigation.

Structural variants occurred in three patients including a chromosome 18q21.1-qter deletion, a chromosome 17p13.1-p13.2-microdeletion and a chromosome 13q31.3-q34 duplication. Monogenic variants were identified in seven patients with the most common being CHD7- mutations that occurred in two patients with CHARGE syndrome.

One patient had neurooculocardiogenitourinary syndrome due to WDR37 mutation, another had MCOPS3 due to a SOX2 mutation, another had MCOPS12-syndrome due to a RARB mutation, another had a MCOPS5-syndrome due to an OTX2-mutation, and another had Lenz microphthalmia syndrome due to a maternally inherited hemizygous BCOR-mutation occurred in single patients respectively. The BCOR-mutation occurred in the patient with an uncle with A. No mutations in PAX6 were found (Table 2).

Biometric data, socket expansion treatment and surgery

The axial length of the bulbs was re-measured in 20 patients using available MRI and CT scans and in one case, ocular ultrasound (Table 2). The use of expanders or prostheses for each child is specified in Table 3.

In all 22/35, children were referred to an ocularist for socket expansion with custom-made conformers to promote eyelid and orbital growth. Clear conformers were fitted in three cases where the child reacted to light or showed a VEP response.

Thirteen children did not need any expansion of the socket and had no prostheses due to mild microphthalmus often with preserved vision (11/13) or general poor health, where expansion/prosthesis was not initiated or wearing one was rejected-(2/13).

Four children had not started expansion at the time of this investigation. Two children did not need expansion but wore prostheses.

Health related quality of life—PedsQL

Parents of 14/22 children completed the PedsQL questionnaire. Five children and two adolescent filled in the questionnaire themselves. Thirteen children were younger than 2 years of age and thus were not eligible. Two children died. Additionally, one family only committed to medical records.

The median total score of parental-reports for-children aged 2–12 was 52.4 (range 22.6–100). The median physical health summary score was 57.8 (range 0–100). The median psychosocial summary score was 57.3 (range 35–100). Nine out of fourteen parents except for two reported lower physical summary scores than psychosocial scores.

Five children and two adolescents aged 5–18 completed the PedsQL self-reports, which resulted in a median total score of 80.4 (range 35.9–96.7). The median physical health summary score was 90.1 (range 25–100) and the median psychosocial summary score was 70 (range 41.7–95). Four of the children had corresponding parental reports. Two of these children reported higher psychosocial and physical summary scores than the parents reported, while for two other children, the parents estimated a greater physical quality of life than the children did (Table 4).

Table 4. Health-related quality of life reported by parents and children according to age

Age groups years	Parental reports (n)	N	Self-reports	N
All age groups
Total score	52.4 (22.6–100)	14	80.4 (35.9–96.7)	7
Physical health	57.8 (0–100)	14	90.1 (25–100)	7
Psychosocial health	57.3 (35–100)	14	70 (41.7–95)	7
Age group 2–4
Total score	52.4 (22.6–100)	8	n/a	0
Physical health	57.8 (0–100)	8	n/a	0
Psychosocial health	57.3 (36.5–100)	8	n/a	0
Age group 5–7
Total score	87 (42.4–90.2)	3	92.9 (89.1–96.7)	2
Physical health	93.8 (31.3–100)	3	96.9 (93.8–100)	2
Psychosocial health	80 (48.3–88.3)	3	90.9 (86.7– 95)	2
Age group 8–12
Total score	48.9 (28.3–72.8)	3	71.7 (35.9–80.4)	3
Physical health	37.5 (15.6–87.5)	3	84.4 (25–100)	3
Psychosocial health	55 (35–65)	3	65 (41.7–70)	3
Age group 18–25
Total score	n/a	0	72.9 (60.9–84.8)	2
Physical health	n/a	0	77.9 (65.6–90.1)	2
Psychosocial health	n/a	0	70 (58.3–81.7)	2

N: number of participants.

Discussion

The purpose of the study was to evaluate and compare visual outcome, ocular pathology, somatic associated morbidities and genetic causative factors in children born with unilateral or bilateral A/M. Further aims were to evaluate the HRQoL in children with A/M.

The main results from the current study show high variability in both the unilateral and bilateral groups of children and adolescents with A/M. Almost one-third (29%) of the cases had total blindness or only light perception. Isolated A/M occurred in 46%, while more than half of the cases (54%) had associated somatic comorbidities, neuroradiological abnormalities and/or neurodevelopmental delay. These comorbidities were more common in the bilateral than in the unilateral group, but the difference was not significant. Among the unilateral cases, those with a normal contralateral eye had a reduced risk of associated problems (p < .01). There was an increased risk of heart defects in children with psychomotor delay when controlled for age, sex, subgroup and ocular diagnosis, odds ratio (OR) of 16.8 (p = .04). Pathogenic genetic abnormalities were identified in 43%. According to parental reports, QoL seemed reduced in children with A/M.

Demographics

In the current study, 9% (3/35) of the children were prematurely born in comparison with 6% (1/18) in patients in another recent Swedish study (20). There was a slight over-representation (26%) of emergency and elective caesarean sections in our study compared to the rate of caesarean sections registered in the Swedish Birth Register 2000–2018 (14.8–17.7%) (21).

There was also a slight predominance for males in our cohort (19 vs 16) although not statistically significant, which accords with the literature (2,20).

Bilateral A/M occurred in 26% of our patients, which is in accordance with the study from the Netherlands where 24% were bilateral (18) but lower than in Hawaii (96 cases) where 45% of the cases were bilateral (4). This may be due to different selection criteria. Taha Najim et al., who included 18 cases, had no bilateral cases (20). Only three patients (9%) in the current study had consanguineous parents as opposed to 47% in another study (22).

Visual function including VEP

Severe visual impairment with amaurosis or light perception was present in 29% of children (10/35). The other, contralateral eye, was normal in 62% of the 26 unilateral cases in this study, compared to the 50% reported by Taha Najim (20).

There were significant mismatches when comparing VEP results with clinical manifestations of the children. For example, two clinically blind children had normal VEP responses. Although the number of performed investigations is very small, this indicates that the VEP method may be unreliable in young children and that the results should be interpreted with caution, especially when discussing visual prognosis with parents.

Somatic comorbidities, neurodevelopmental disorders and neuroradiological findings

A/M occurred as an isolated finding in 46% of the cases. Genetic testing was normal, had not been performed, or had not been considered clinically necessary in these children. It can be discussed whether repeated future genetic analysis-could reveal new mutations in these cases. Neurodevelopmental problems can also become evident with increasing age.

The majority of the cases, 54%, were non-isolated, and the children suffered from systemic extraocular malformations, functional impairments and/or cerebral pathology. This is within the previously described range of 32.1–61.1% (5,18,20). However, systemic involvement was more common in bilateral (78%) than in unilateral cases (50%), but the difference was not significant unlike a previous Swedish study in which bilateral cases had more frequent systemic involvement (2).

The most common somatic anomalies in our study were cardiac defects, which occurred in 26% of all cases. The prevalence of hearing impairment was 14%, and the prevalence of psychomotor or speech delay or intellectual disabilities was 37%. All numbers are in line with the study by Taha Najim et al., who reported cardiac defects in 25%, hearing impairment in 12% and psychomotor delay in 31% of cases. This is somewhat surprising as their study material-consisted of only unilateral cases. Brain pathologies were found in 40% of our cases after imaging with ultrasound, MRI or CT, while Taha Najim et al. reported 25% (20).

Genetic pathology

Pathogenic genetic abnormalities occurred in 42% of the tested cases, which is in the same range as previous studies (20–61%) (4,7,20,23) and higher than in the study by Shah et al. (9). Genetic testing was normal or had not been considered clinically necessary in the other cases. It is open to discussion as to whether in these cases, repeated future genetic analysis could reveal new mutations.

Two patients in our study had genetically confirmed CHARGE syndrome (14), while one patient had a SOX2 mutation. This differs from Groot and co-workers who reported that four bilateral cases (out of 58) had a SOX2 mutation (18).

One limitation of this study could be that only 24/35 patients who underwent genetic screening as referrals were only sent when genetic investigation was part of clinical practise. Also, the type of genetic investigation differed between different patients. If more extensive genetic investigations with WGS screening were conducted for all patients, it is possible that a genetic cause of A/M would be found in a greater number. Identification of a genetic cause is important information for patients with A/M and their parents, as it may alter the prognosis and management. It would also permit genetic counselling and prenatal testing for parents who are planning for another child.

One patient had congenital toxoplasmosis. However, TORCH panels were only performed in a few children. Environmental factors such as congenital infections with toxoplasma gondii and cytomegalovirus, for example, but as well as herpes simplex, influenza, coxsackie and Zika viruses and parvovirus 19 (24) can be causative to A/M, as can maternal diabetes (7) or vitamin A deficiency, exposure to X-rays, solvent misuse and thalidomide exposure (1).

Health-related quality of life PedsQL

In this study, both parental reports and self-reports resulted in variable findings about HR QoL, but the majority of the cases indicated a significant reduction in HR QoL. We were unable to make further comparisons because there were only four corresponding self and parental reports.

Previous studies also had similar results, with reduced HR QoL and a greater impact on the psychosocial domain than on the physical well-being reported by the children compared to the parental reports (25–27). This will be further investigated in deep interviews in future studies.

Conclusion

In conclusion, children born with bilateral and unilateral anophthalmia or microphthalmia were at risk of not only visual impairment but also somatic, neurodevelopmental and/or genetic comorbidities. As associated morbidities and delayed psychomotor development may be difficult to assess in small children, a multidisciplinary approach and regular follow-ups throughout childhood and adolescence are important.

Since genetic defects seem to be of great importance not only in bilateral A/M but also in unilateral A/M, we suggest that all patients should undergo genetic evaluation.

Clinical guidelines for the diagnosis and treatment of patients with anophthalmia or microphthalmia adapted from Ragge et al. (16)

• Suspicion of microphthalmia if the horizontal corneal diameter is <9 mm in neonates

• Diagnosis of microphthalmia, if the axial length of the bulb is <15.8 mm on ultrasound or MRI in a neonate

• Refer to a paediatric ophthalmologist

• Refer to oculoplastics and prosthetics unit if bulb length is <16 mm neonatally.

• MRI of the brain and orbits to detect pathology and measure axial length

• VEP in selected cases, but the results should be interpreted with caution

• Multidisciplinary approaches including paediatricians and ear, nose and throat specialists.

• Long-term follow-up is needed as associated comorbidities in the other eye or other organs and psychomotor delay or behavioural problems may not be evident in the neonatal period

• Genetic evaluation is strongly recommended both in children born with unilateral or bilateral microphthalmia/anophthalmia

Acknowledgments

We would like to thank ocularists Eva Johansson, Anna Povse, Niklas Schesny and Benjamin Rosenberg for evaluating the questionnaires as well as Associate Professor Britt Marie Anderlid for reading the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

We are grateful to Ögonfonden for funding.