Fetal chondrodysplasia punctata associated with maternal autoimmune diseases: a review

Figures & data

Table 1 Clinical and radiologic features of infants born to mothers affected with SLE

Clinical features	Costa et al^Citation15 Skeletal dysplasia meeting 1993 Chitayat et al^Citation19	Mansour et al^Citation20	Elcioglu et al^Citation21	Elcioglu et al^Citation21	Austin-Ward et al^Citation22	Kelly et al^Citation23	Kozlowski et al^Citation24	Kozlowski et al^Citation24	Shanske et al^Citation25	Chitayat et al^Citation19	Chitayat et al^Citation19	Tim-aroon et al^Citation26	Roy et al^Citation27
Gestational age	29 weeks	25 weeks dizygotic twin	Still born at 36 weeks	Still born at 24 weeks	33 weeks	33 weeks+5 days	7 months	Term	36 weeks	IUFD at 21 weeks	35 weeks	37 weeks	Term
Gender	Female	Male	Male	Male	Female	Male	Male	Male	Male	Male	Male	Male	Male
Parental ethnic origin	Sri Lanka	West Indian	Black African	Black African	Chilean	African American	Cape town	Cape Town	Dominican republic	German	Caucasian	Thailand	Indian Hindu
Consanguinity	Not consanguineous	Not consanguineous	Not consanguineous	Not consanguineous	Not consanguineous	Not reported	Not consanguineous	Not consanguineous	Not consanguineous	Not consanguineous	Not consanguineous		Not consanguineous
Maternal disease	SLE diagnosed prenatally	SLE diagnosed postnatally	SLE	SLE	SLE diagnosed at 16 years	SLE diagnosed postnatally	SLE diagnosed in early adulthood	SLE	SLE diagnosed postnatally	SLE	SLE	SLE	SLE diagnosed postnatally
Medications in pregnancy	Prednisone	None	Intermittent steroid use	• Prednisone • Aspirin	• Hydroxychloroquine • Aspirin • Prednisolone	Not applicable	Chloroquine Prednisone	• Quinine • Chloroquine • Epanutin		• Prednisone • Azathioprine • Hydroxychloroquine sulfate • Methyldopa • Amlodipine	Prednisone	• Prednisolone • Fraxiparin	No medications
Mother’s antibodies	• Positive anti-Ro and anti-La antibodies • Positive anti-RNP antibodies • Positive ANA	Not reported	Not reported	Not reported	• Positive ANA • Positive anticardiolipin antibodies • Positive ENA • Positive RNP • Positive anti-Ro • Positive anti-dsDNA	Positive ANA Positive RNP Negative for Sm, Ro, La and dsDNA antibodies	Not reported	Not reported	• Positive ANA • Positive anti-RNP antibodies • Positive anti-RO and anti-LA antibodies	Not reported	Not reported	• Positive ANA • Positive anti-RO and anti-La antibodies • Positive anti-RNP • Positive anticardiolipin • Positive anti-dsDNA	• Positive ANA • Positive anti-SM antibodies • Positive anti-RNP • Positive anti-Ro antibodies
Pregnancy history	Not reported	Uneventful	Anatomy scan showed nasal hypoplasia, short long bones (below third centile), a sacral abnormality and polyhydramnios	• Maternal flare-up of SLE renal failure, hypertension and neurologic impairment • Anatomy scan showed femoral length below third centile	Not reported	No prenatal care before 30 weeks gestation	Not reported	Epilepsy	UTI	High blood pressure Anatomy scan showed short long bones and an abnormal head shape	Anatomy scan showed discrepancy of 4 weeks in femoral length and 2 weeks in humeral length	Not reported	Uneventful No exposure to infection
Birth weight	Below third centile	820 g (50%)	1485 g (below fifth centile)	190 g (below fifth centile)	1500 g	1.8 kg	2020 g	3080 g	2176 (25th centile)	127 g	Not reported	2970 g (50th centile)	2459 g (10th–25th centile)
Birth HC	Not reported	Not reported	31cm (10th centile)	16 cm (below fifth centile)	Not reported	30.5 cm	33 cm	38 cm	33 cm (50th centile)	Not reported	Not reported	35 cm (75th centile)	33 cm (50th centile)
Birth length	Not reported		27.5 cm (below fifth centile)	20.7 (below fifth centile)	39.5 cm	42 cm	33 cm	34 cm	42 cm (below 10th centile)	Not reported	46 cm (50th centile)	45 cm (10th centile)	42.5 cm (below 10th centile)
Pattern of stippling	Stippling at: • The proximal femoral epiphyses • Both heels	Stippling at: • The lumbosacral spine • The proximal end of second metacarpals	Stippling at: • The laryngeal cartilage • Anterior and lateral to the vertebral bodies • The proximal femora • The elbows • The ends of the first, second, third and fourth metacarpals • The tarsal bones and the proximal ends of the first, second and third metatarsals	Stippling at: • The laryngeal cartilage • The anterior spinous ligament • The anterior part of the vertebral body • The distal end of the humeri and proximal ends of the femora • The tarus	Stippling at: • Sacrococcygeal region • Heels	Stippling at • The right proximal humerus • Sacrum • Distal phalanges • Tarsal centers	Stippling at • The tarsal regions • Spine	Stippling at: • Epiphyses of the knees • Tarsal regions • The pine • Left wrist and terminal phalanges	Stippling at: • Vertebral bodies • Carpal bones and phalanges • The shoulders and hips • The elbows and knees • All of the tarsal bones and phalanges	Stippling at: • The vertebral column • The sacral ossification centers	Multiple stippled epiphyses	Stippling at: • The proximal humeri • Elbows • Metacarpals • Hips • Knees • Vertebrae	Stippling at: • The shoulders • The elbow • The hips • The knee joints • Anterior arch of foramen magnum
Vertebral body defects	Not reported	Sagittal clefts	Sagittal clefts of several upper thoracic vertebral bodies	Coronal clefts	Not reported	Not reported	• Round and irregular • Anterior wedges	Hypoplasia and dysplasia of vertebral bodies	• Decreased ossification • Small vertebrae with vertical clefts	Nor reported	Not reported	• Non-ossification of the vertebral bodies of cervical spines • Partially ossified thoracic and lumbosacral vertebral bodies • Wedge-shaped midthoracic vertebrae • Sagittal cleft of lumbar vertebrae	• The spine exhibited minimal ossification • Coronal clefts of the vertebral bodies
Other radiologic findings	None	• Tiny distal phalanges • Sort second metacarpals	• Short long bones (below fifth centile) • Pronounced humeral shortening • Poorly ossified skull vault	• Short long bone (below the fifth centile) • Poor ossification of the vault • Short first metatarsals • Short third and fourth metacarpals	Not reported	• Brachydactyly • Deformity of the proximal phalanges of the first and second digits • Deformity of the proximal phalanx of the great toe	• Generalized osteopenia • Hypoplastic distal phalanges	Short dysplastic terminal phalanges	• Short tibias • Unusual cartilaginous extensions from the tibial growth plate into the upper tibias	• Bell-shaped chest • Mild bowing of the tibiae and femora • Shortening of the middle phalanges, the first metacarpal and the proximal phalanx of the thumbs bilaterally • The second, third and fourth distal phalanges bilaterally showed broadened tufts with proximal tapering • Increased density at the bases of the third distal phalanges	Asymmetric femur length		• Rhizomelic shortening of extremities • Metaphyseal flaring in humerus and femur
Facial features	• Flattened nose • Skin tag on the left cheek	• Nasal hypoplasia • Depressed nasal bridge • Anteverted nares • Bilateral alar grooves	Poorly developed nasal bridge		• Poorly developed brow ridges • Depressed nasal bridge • Nasal hypoplasia • Large philtrum • Thin pinnae • Prominent occiput	• Small ears • Upward-slanting palpebral fissures • Midface hypoplasia • Short columella	• Narrow face • Prominent ears • Mandibular prognathism • Crowded teeth	• Prominent forehead • Simple ears • Midface hypoplasia • Depressed nasal bridge • Micrognathia	• Upward palpebral fissures • Epicanthal folds • Midface hypoplasia • Depressed nasal bridge • Hypoplastic nasal bone • Anteverted nares	• The nose was flat • The chin was prominent	• Broad low nasal bridge • Long philtrum • Thin upper lip • Micrognathia	• Flattened nasal bridge • Hypoplasia of the nasal bone • Midface hypoplasia • Thin upper lip • Long/smooth philtrum	• Midface hypoplasia • Depressed nasal bridge • Anteverted nares • Cataracts in both eyes
Skin rash	Lupus facial rash	Not reported	Not reported	Not reported	Erythematoviolaceous, scaly facial rash	Lupus rash over the neck, wrists, ankles and anterior thorax	Not reported	Not reported	Not reported	Not reported	Not reported	Erythematous lupus rash over face, trunk and extremities	Not reported
Musculoskeletal exam	Not reported	Brachydactyly with drum stick swelling	• Symmetrical, mild limb shortening • Short fingers and camptodactyly • The toes overlapped with hypoplastic nails on the feet	• The limbs are slightly short • Short, malpositioned fingers • Underdeveloped right palmar creases	Not reported	• Generalized hands brachydactyly • Short first, second and fourth proximal phalanges	Pectus excavatum	• Rhizomelia of the upper and lower limbs • Brachydactyly • Talipes equinovarus • Short and bell-shaped thorax	• Rhizomelic shortening of the arms and legs • Bilateral brachydactyly of the second and third fingers	Short limbs		• Small thorax • Pectus carinatum • Wide internipple distance • Mild rhizomelia of the upper and lower extremities • Decreased U/L segment ratio • Severe kyphosis of the thoracic spine	• Barrel-shaped chest • Proximal shortening of both the upper and lower limbs
Developmental history	Normal	Normal development at 15 months	Not reported	Not reported	Not reported	Not reported	Intellectual delay	Developmental delay	Mild psychomotor delay with borderline cognitive function	Not reported	Normal	Appropriate for age	Not reported
Growth parameters	Proportionally small	Not reported	Not reported	Not reported	Not reported	At 35 months • Weight and height below fifth centile • HC was below 10th centile	Not reported	Not reported	Height and weight below third centile	Not reported	At 5 months of age: • Height was 54.5 cm (−4.5 SD) • Weight 6.6 kg (25th centile) • HC 41.5 cm (40th centile)	• Progressive kyphosis • At the age of 3 years: 1. Height 80 cm (below third centile) 2. Weight 11.4 kg (third centile) 3. HC 49 cm (50th centile)	Not reported
Chromosomal analysis	Not reported	46, XY	Not performed	Not performed	46, XX	46, XY	46, XY	46, XY	Not reported	Not reported	Not reported	46, XY	Not reported
Metabolic work up	Not reported	Not reported	Not performed	Not performed	Not reported	VLCFA normal	Not done	Not done	• Normal plasmalogen level • Normal VLCFA • Normal total plasma lipids • Normal phytanic acid level	Not reported	Not reported	• Normal VLCFA • Normal plasmalogen	• Normal plasmalogen • Normal VLCFA • Normal phytanic acid
Antibodies level	Not reported	Not reported	Not reported	Not reported	Not reported	Positive ANA Positive anti-RNP	Not reported	Not done	Not reported	Not reported	Not reported	• Positive anti-Ro and anti-La antibodies • Positive anti-RNP • Positive ANA antibodies	Not reported

Abbreviations: ANA, antinuclear antibody; dsDNA, double-stranded DNA; HC, head circumference; IUFD, intrauterine fetal death; RNP, ribonucleoprotein antibodies; SLE, systemic lupus erythematosus; UTI, urinary tract infection; VLCFA, very long chain fatty acid.

Table 2 Clinical and radiologic features of infants born to mothers with mixed connective tissue diseases

	Costa et al^Citation15 Skeletal dysplasia meeting 1993 Chitayat et al^Citation19	Chitayat et al^Citation19	Chitayat et al^Citation19	Curry et al David Smith meeting 1993^Citation14 Chitayat et al^Citation19	Curry et al David Smith meeting 1993^Citation14 Chitayat et al^Citation19	Schulz et al^Citation30	Schulz et al^Citation30
Gestational age	36 weeks	Fetal demise at 22 weeks	34 weeks	32 weeks	32 weeks	34 weeks	37 weeks
Gender	Male	Male	Female	Female	Female	Female	Male
Paternal ethnic origin	Caucasian	Liberian	Not reported	African-American	African-American	Not reported	Not reported
Consanguinity	Not consanguineous	Not consanguineous	Not consanguineous	Not consanguineous	Not consanguineous	Not consanguineous	Not reported
Maternal disease	MCTD	MCTD	MCTD	MCTD	MCTD	MCTD	MCTD
Medications in pregnancy	• Prednisone • Verapamil	Not reported	• Amlodipine • Fexofenadine hydrochloride • Acetazolamide	Prednisone	Prednisone	Not reported	Not reported
Mother’s antibodies		• Positive ANA • Positive anti-RNP • Positive anti-RO	• Positive ANA • Positive anti-RNP	• Positive ANA • Positive anti-RNP	• Positive ANA • Positive anti-RNP	• Positive ANA • Positive anti RNP	• Positive for ANA • Positive for anti-RNP
Pregnancy history	Skin rash and arthralgia in the third trimester	• Maternal flare up at 22 weeks’ gestation • Fetal demise at 22 weeks	• A fetal ultrasound at 20 weeks’ gestation showed • Epiphyseal stippling • Flat vertebrae • Nasal bone hypoplasia	Not reported	Not reported	• Gestational diabetes • Hypertension • Anatomy scan showed: • Depressed nasal bridge • Epiphyseal stippling of the long bones	• Gestational DM • Hypertension • Fetal U/S showed: • Depressed nasal bridge • Stippled epiphyses
Birth weight	2080 g (third centile)	584 g	Not reported	1700 g (50th centile)	1.32 kg (10th centile)	1980 g (10th–50th centile)	2608 g
Birth HC	Not reported	Not reported	Not reported	30 cm (25th centile)	29.5 cm (25th centile)	33 cm (50th−90th centile)	Not reported
Birth length	43 cm (below third centile)	Not reported	Not reported	42 cm (below third centile)	38 cm (below third centile)	40.6 cm (3rd−10th0020centile)	45.7 cm
Pattern of stippling	Stippling at: • Proximal humeri • Proximal femoral heads • Vertebral bodies	Stippling: • Cervical and thoracic vertebrae • Proximal femurs and Taluses	Stippling at: • Feet • Hips • Vertebrae • Sacrum	Stippling at: • Tarsal bones • Sacrum • Vertebral body • Greater trochanter bilaterally • The base of distal phalanges	• Stippled proximal femoral epiphysis • Stippled metacarpals and calcanei bones • Stippled vertebral bodies	• Stippling in the left proximal humerus • Stippling of both proximal femora • Stippling of carpal and tarsal bones • Stippling of multiple vertebral bodies	• Stippling of humeri • Stippling of femura
Vertebral body defects	Coronal clefts	Not reported	Not reported	• Vertical clefts of T3, T6 and T8 vertebral bodies • Broad flat L5 vertebra	Not reported	• Kyphosis • Asymmetric vertebrae • Coronal clefts • Odontoid hypoplasia	• Platyspondyly • Clefts at multiple levels
Other radiologic findings	Not reported	• Hypoplasia of the distal phalanges • Generalized brachydactyly	• Hypoplasia of the distal phalanges • Brachydactyly	• Short first, second and fourth distal phalanxes bilaterally • Cone-shaped epiphyses in the distal phalanges of the thumbs • Mild shortening of the middle phalanx of the index finger	Not reported	• Short second proximal phalanx bilaterally	Short proximal and middle phalanges of the second digits
Facial features	• Upturned nares • Retrognathia • Long philtrum • Hypoplastic nose	• Nasal hypoplasia • Malar hypoplasia	• Large anterior and posterior fontanelles • Flattened nasal bridge • Short nose	• Nasal hypoplasia • Large anterior fontanelle • Long philtrum • Small ears	• Prominent eyes • Displaced inner canthi • Flat nasal bridge • Nasal hypoplasia • Small unilateral cortical cataract	• Flat nasal bridge • Shortened columella	• Midface hypoplasia • Flat nasal bridge
Skin rash	Not reported	Not reported	Not reported	None	None	Not reported	Not reported
Musculoskeletal exam	• Narrow chest • Hip contractures • Hyperextended left knee • Overlapping fingers • Club feet		• Brachydactyly • Radial deviation of the distal phalanges • Bilateral shortened first toes • Prominent thorax	• Radially deviated index fingers • Short proximal phalanges • Short first metatarsals • Flat feet • Joint hypermobility • Mild pectus carinatum	• Hypoplasia of the distal phalanges • Clinodactyly of the second fingers • Hypoplastic finger and toenails • Mild rhizomelic shortening of the humeri	• Rhizomelic shortening of the extremities	• 4 limbs rhizomelia • Bowed humerus • Broad phalanges • Short second metacarpals and first metatarsals • Pectus excavatum
Developmental history	Developmental delay	Not reported	Not reported	Normal	• Normal development • Unilateral sensory neural hearing loss	• Normal motor development • Mild speech delay	Normal development
Growth parameters	Not reported	Not reported	At 7 weeks: • Length on 10th–25th centile • Weight on 50th–75th centile • HC on 90th centile	At age 7–10 years: • Height 118 cm (10th centile) • Weight 34 kg (95th centile)	Normal	At 18 months: • Weight on10th centile • Height on third centile	Not reported
Chromosome analysis	Not reported	46, XY	46, XX	Not reported	46, XX	46, XX	Not reported
Metabolic work up	Not reported	Not reported	Normal blood cholesterol levels	Not reported	Not reported	• Normal plasmalogen • Normal phytanic acid • Normal very long chain fatty acid • Normal sterol panel	Not reported
Antibodies level	Not reported	Not reported	Not reported	Not reported	• Positive ANA • Positive anti-Ro • Positive anti-RNP • Positive anticardiolipin antibodies	Not done	Not done

Abbreviations: ANA, antinuclear antibody; DM, diabetes mellitus; HC, head circumference; MCTD, mixed connective tissue disease.

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