Inherited bone marrow failure syndromes in adolescents and young adults

Figures & data

Table I. Examples of inherited bone marrow failure syndromes (IBMFS).

Disease	Hematologic manifestation	Pathway disrupted
Fanconi anemia	Pancytopenia	DNA repair
Dyskeratosis congenita	Pancytopenia	Telomere maintenance
Diamond–Blackfan anemia	Red cell aplasia	Ribosome biogenesis
Thrombocytopenia absent radii syndrome	Thrombocytopenia	mRNA processing and export
Severe congenital neutropenia	Neutropenia	Protein folding/trafficking
Shwachman–Diamond syndrome	Pancytopenia	Ribosome maturation
Congenital amegakaryocytic thrombocytopenia	Thrombocytopenia	Growth factor receptor signaling
Familial platelet disorder with propensity to AML	Thrombocytopenia	Transcriptional regulation
MonoMAC and related GATA2 deficiency disorders	Monocytopenia and lymphopenia	Transcriptional regulation

Figure 1. Phenotypic features of Fanconi anemia (FA). (A) Hypoplastic thumbs in an 11-year-old. (B) Hypopigmented (white arrow) and hyperpigmented (black arrows) skin lesions on the trunk of an adolescent. Photograph courtesy of Susan J. Bayliss, MD. (C) Progressive aplastic anemia in a 20-year-old with FA. Most of the marrow space is occupied by fat.

Table II. Congenital and developmental anomalies associated with Fanconi anemia (FA) (3,95).

Anomaly	% Affected
Skin (pigmentation changes)	55–64
Short stature	51–63
Upper limb	43–49
Testis	20–32
Eye	23–38
Kidney	21–34
Head (microcephaly and other anomalies)	26
Developmental disability	11–16
Birth weight < 2500 g	11
Ears (hearing loss)	9–11
Heart and lungs	6–13
Gastrointestinal tract	5–14

Figure 2. Phenotypic features of dyskeratosis congenita (DC). (A) Nail dystrophy (arrow) in an adolescent. (B) Oral leukoplakia in an adult. (C) Skin changes in an adult. Hypopigmented lesions and the typical reticular rash of DC are evident on the upper chest (black arrow). Hypopigmentation is more pronounced in the sun-damaged skin of the neck (white arrow). (D) and (E) Pulmonary fibrosis on chest radiograph and CT scan of an adult. Photographs courtesy of Susan J. Bayliss, MD, and William H. McAlister, MD.

Table III. Prevalence of clinical features in patients with classic dyskeratosis congenita (DC) (3,22,95).

Clinical feature	% Affected
Diagnostic mucocutaneous features:
Skin pigmentation changes	88–89
Nail dystrophy	73–88
Leukoplakia	64–78
Eye abnormalities, excessive tearing	31–38
Pulmonary fibrosis	20
Learning difficulties or developmental delay	14–25
Teeth abnormalities	17–19
Hair loss or early graying	16–18
Hyperhidrosis	10–15
Short stature	14
Gastrointestinal abnormalities (liver fibrosis, esophageal strictures, ulcers, malabsorption)	14
Malignancy	10–12
Microcephaly	8
Urinary tract abnormalities (urethral stricture, phimosis)	7
Cerebellar hypoplasia, ataxia	7
Gonadal abnormalities (hypogonadism, cryptorchidism)	1–5

Figure 3. Phenotypic features of Diamond–Blackfan anemia (DBA). (A) Abnormal thumb in an adult with an RPL11 mutation. (B) Muscular ventricular septal defect. Note the blood flow across the defect. LV = left ventricle; RV = right ventricle. Echocardiogram courtesy of Patrick Jay, MD, PhD.

Table IV. Congenital and developmental anomalies associated with Diamond–Blackfan anemia (DBA) (35,96–98).

System	Range of anomalies	% Affected
Skeletal	Short stature	30–33
Head, face, palate	Hypertelorism, cleft palate, high arched palate, microcephaly, micrognathia, microtia, low-set ears, low hairline, epicanthus, ptosis, flat broad nasal bridge	21–36
Upper limb	Triphalangeal, duplex or bifid, hypoplastic thumb, syndactyly, absent radial artery	9–21
Renal, urogenital	Absent kidney, horseshoe kidney, hypospadias	7–19
Cardiopulmonary	Ventricular or atrial septal defects, coarctation of the aorta, complex cardiac anomalies	7–15
Eyes	Congenital glaucoma, strabismus, congenital cataract	12
Neck	Short neck, webbed neck	10
Brain	Learning difficulties	7

Figure 4. Phenotypic features of thrombocytopenia with absent radii (TAR) syndrome. (A) Absence of the radius. (B) Late-onset MDS in an adolescent with TAR syndrome (see Vignette 6). Radiograph courtesy of William H. McAlister, MD.

Table V. Congenital and developmental anomalies associated with Shwachman–Diamond syndrome (SDS) (70,99,100).

Feature	% Affected
Hematologic
Neutropenia	77–100
Severe neutropenia (< 500/μL)	23–67
Anemia	17–66
Thrombocytopenia	24–70
Gastrointestinal
Exocrine pancreatic insufficiency	85–100
Elevated transaminases	45–100
Skeletal abnormalities
Metaphyseal dysostosis	41–100
Rib cage abnormalities	12–92
Short stature	52–95

Figure 5. Phenotypic features of Shwachman–Diamond syndrome (SDS). (A) MRI showing fatty infiltration of the pancreas (white arrow). (B) Metaphyseal dysostosis (black arrows). Images courtesy of William H. McAlister, MD.

Shimamura A, Alter BP. Pathophysiology and management of inherited bone marrow failure syndromes. Blood Rev. 2010;24:101–22.

 PubMed Web of Science ®Google Scholar

Alter BP. Inherited bone marrow failure syndromes. In: Nathan DG, Orkin SH, Ginsburg D, Look AT, editors. Nathans and Oski’s Hematology of infancy and childhood. 6th ed. Philadephia: Saunders; 2003. p. 281–365.

 Google Scholar

Vulliamy T, Dokal I. Dyskeratosis congenita. Semin Hematol. 2006;43:157–66.

 PubMed Web of Science ®Google Scholar

Lipton JM, Atsidaftos E, Zyskind I, Vlachos A. Improving clinical care and elucidating the pathophysiology of Diamond Blackfan anemia: an update from the Diamond Blackfan Anemia Registry. Pediatr Blood Cancer. 2006;46:558–64.

 PubMed Web of Science ®Google Scholar

Smith OP, Hann IM, Chessells JM, Reeves BR, Milla P. Haematological abnormalities in Shwachman-Diamond syndrome. Br J Haematol. 1996;94:279–84.

 PubMed Web of Science ®Google Scholar

Cipolli M, D’Orazio C, Delmarco A, Marchesini C, Miano A, Mastella G. Shwachman’s syndrome: pathomorphosis and long-term outcome. J Pediatr Gastroenterol Nutr. 1999;29:265–72.

 PubMed Web of Science ®Google Scholar

Myers KC, Bolyard AA, Otto B, Wong TE, Jones AT, Harris RE, et al. Variable Clinical presentation of Shwachman-Diamond syndrome: update from the North American Shwachman-Diamond Syndrome Registry. J Pediatr. 2014;164:866–70.

 PubMed Web of Science ®Google Scholar