recurrent infections

Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome 3

Clinical Characteristics
Ocular Features: 

Patients have been described as having variable oculofacial features including epicanthal folds, hypertelorism, strabismus, and 'tapetoretinal degeneration'.    

Systemic Features: 

The full phenotype is variable and unknown based on the 5 reported patients from 4 families of whom 3 were consanguineous.  Recurrent infections (especially respiratory and otitis media) seem to be among the most consistent features.  Others include intrauterine growth retardation, developmental delay including psychomotor delays, a flat midface with various anomalies, low-set ears, renal dysgenesis, polydactyly, severe agammaglobulinemia, hypospadias, and cryptorchidism.  Normal T-cell function and normal B cells are present.  Conductive hearing loss, polydactyly, and scoliosis may be features as well.  Two of the 5 reported patients with ICF3 were reported to have mental retardation.  One patient died at the age of 26 years.

Genetics

Homozygosity of CDCA7 (2q31.1) mutations with centromeric instability and hypomethylation of selected juxtacentromeric heterochromatin regions is responsible for this (ICF3) autosomal recessive condition.  There is genetic heterogeneity in ICF (ICF1, ICF2, ICF3, and ICF4 [see 242860).   

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome

Thijssen PE, Ito Y, Grillo G, Wang J, Velasco G, Nitta H, Unoki M, Yoshihara M, Suyama M, Sun Y, Lemmers RJ, de Greef JC, Gennery A, Picco P, Kloeckener-Gruissem B, Gungor T, Reisli I, Picard C, Kebaili K, Roquelaure B, Iwai T, Kondo I, Kubota T, van Ostaijen-Ten Dam MM, van Tol MJ, Weemaes C, Francastel C, van der Maarel SM, Sasaki H. Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome. Nat Commun. 2015 Jul 28;6:7870.

PubMed ID: 
26216346

Retinopathy with Neutropenia

Clinical Characteristics
Ocular Features: 

Pigmentary retinopathy was reported in a 25 year old female with moderately reduced visual acuity. Rare bone spicules pigment deposits were present in the periphery and macular edema was noted. Severely reduced scotopic and photopic responses were recorded.

Systemic Features: 

The single reported individual had congenital neutropenia and microcephaly. She had evident growth retardation and microcephaly at birth with subsequent recurrent upper respiratory infections and gingivitis. Speech and motor development were normal. Short stature was noted as well. The limbs were described as slender as in Cohen syndrome (216550) but no truncal obesity or joint hypermobility was present. The facial dysmorphism only vaguely resembled that found in Cohen syndrome (216550).

Genetics

This is a newly described condition whose unique identity remains to be established since only a single patient has been reported. This patient carried two heterozygous splicing mutations in the same VPS13B gene, the same gene in which more than 100 homozygous mutations have been found in individuals with Cohen syndrome (216550). Each parent carried a different splicing mutation in VPS13B.

Cohen syndrome (216550) however, has additional phenotypic features such as truncal obesity, intellectual disabilities, intermittent neutropenia, microcephaly, facial dysmorphism, myopia, and progressive chorioretinal dystrophy. Variable amounts of neutropenia were observed from age 5 years but the marrow was normocellular in appearance.

Isolated retinopathy with neutropenia may or may not be an autosomal recessive variant of Cohen syndrome (216550).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Chédiak-Higashi Syndrome

Clinical Characteristics
Ocular Features: 

The ocular hypopigmentation and visual function deficits in Chediak-Higashi syndrome resembles that of other types of albinism.  The iris has transillumination defects and the retina is hypopigmented.  Patients are photophobic and often have nystagmus.  Due to the early mortality of many patients, vision is difficult to measure, but is said to range from normal to near normal.  Hair bulb incubations studies show normal pigmentation.

A  subset of patients with later onset of disease has been reported to have optic atrophy, thinning of the nerve fiber layer, and a central scotoma.

Systemic Features: 

This is a form of albinism with other systemic features such as adenopathy, hepatosplenomegaly, neutropenia, and susceptibility to infection (especially gram positive organisms).  The hypopigmentation is evident at birth but may be patchy.  The hair has been described as having a blue-green metallic sheen.  It may also be sparse.  Patients have an increased risk of leukemia and lymphoma-like disease.  Peripheral sensory-motor neuropathy and ataxia are common in older individuals.  Thrombocytopenia can lead to easy bruising and extensive bleeding.  Neutrophils are often few in number and deficient in chemotactic and bacterial activity.  Pyoderma and peridontitis can be severe.  Survival without treatment is between 3 and 4 years but those who survive eventually develop lymphohistiocytic infiltration of major organs, bone marrow and peripheral nerves as young adults.

Giant peroxidase-positive inclusions in white blood cells are diagnostic.

Genetics

This is an autosomal recessive disorder caused by mutations in the LYST gene (1q42.1-q42.2) causing defects in vesicle trafficking.

Hermansky-Pudlak syndrome (214500) is another form of hypopigmentation with serious systemic manifestations.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Bone marrow transplantation can prolong life but neurologic symptoms often develop in those who survive.  Low-vision aids can be helpful.  Infections, of course, should be promptly and vigorously treated.

References
Article Title: 

Optic neuropathy in late-onset neurodegenerative Chédiak-Higashi syndrome

Desai N, Weisfeld-Adams JD, Brodie SE, Cho C, Curcio CA, Lublin F, Rucker JC. Optic neuropathy in late-onset neurodegenerative Chediak-Higashi syndrome. Br J Ophthalmol. 2015 Aug 25. pii: bjophthalmol-2015-307012. doi: 10.1136/bjophthalmol-2015-307012. [Epub ahead of print].

PubMed ID: 
26307451

Chédiak-Higashi syndrome

Kaplan J, De Domenico I, Ward DM. Chediak-Higashi syndrome. Curr Opin Hematol. 2008 Jan;15(1):22-9. Review. PubMed PMID: 18043242.

PubMed ID: 
18043242
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