HHS

Hoyeraal-Hreidarsson Syndrome

Clinical Characteristics
Ocular Features: 

Little is known about the ocular signs in this rare disorder.  As many patients have systemic features of dyskeratosis congenita, however, it is possible that some of the ocular findings such as conjunctival and corneal scarring and lid margin distortion might be similar.  Hoyeraal-Hreidarsson syndrome, though, is a more severe disease and many infants may die before the mucocutaneous manifestations appear.  At least one patient has had an exudative retinopathy similar to that seen in Revesz syndrome (268130).  Epiphora and a preretinal hemorrhage have also been reported.

Systemic Features: 

Features of pancytopenia usually appear after 5 months of age while growth retardation and microcephaly are evident soon after birth.  The marrow may show progression to myelodysplasia.  Birth weight is usually low.  Truncal ataxia and axial hypotonia have been reported and MRI imaging reveals cerebellar hypoplasia.  Global developmental delay is a common feature and a few patients have seizures.  Susceptibility to infection has been noted but the basis for an immunodeficiency remains elusive.  Some patients have signs of dyskeratosis congenita such as sparse hair, nail dysplasia, and a reticular pattern of skin pigmentation.

Genetics

This is an X-linked disorder resulting from mutations in the DKC1 gene (Xq28) active in telomere maintainence.  As expected, the vast majority of affected individuals are male but at least 3 females have been reported. The same gene is also mutated in the X-linked form of dyskeratosis congenita (305000) suggesting that the two are allelic or that both are the same disease.  There are clear clinical differences, however, as severe developmental delay, immunodeficiency, cerebellar hypoplasia, and microcephaly are generally not present in the latter disorder.

There is evidence for telomere length variations in this syndrome and in dyskeratosis congenita.  Homozygous mutations in RTEL1 (regulator of telomere length helicase 1) (20q13.33) have also been found in these conditions.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

CHARGE Syndrome

Clinical Characteristics
Ocular Features: 

Both ocular and systemic abnormalities are highly variable, even within families.  Among the most common ocular features are unilateral or bilateral ocular colobomas (80%).  These involve the iris most frequently but they may extend into the posterior chamber and rarely involve the optic nerve.  A significant number of patients with uveal colobomas have an associated microphthalmia.  The lid fissures often slant downward.  A few patients have congenital cataracts, optic nerve hypoplasia, persistent hyperplastic vitreous, and strabismus.

Systemic Features: 

A wide variety of systemic anomalies have been reported.  Congenital heart defects (primarily septal) and CNS malformations are among the most common features, reported in 85% and 55% respectively.  Tetralogy of Fallot is considered by some to be the most common heart malformation.  Growth and mental retardation are found in nearly 100%.  The pinnae are often set low and hearing loss is common.  Ear anomalies, both internal and external, have been described in 91%, and some degree of conduction and/or sensorineural deafness is present in 62%.  Choanal atresia is found in at least 57% of patients.  This along with cleft palate and sometimes esophageal atresia or reflux often contributes to feeding difficulties which are common in all age groups.  Cranial nerve deficits are seen in 92% of patients and more than one nerve is involved in nearly 3 of 4 patients.  The most common cranial nerve defects involve numbers IX, X, VIII, and V.  Facial palsies are an especially important feature. Hypogonadotropic hypogonadism and underdevelopment of the external genitalia are often seen, especially in males.  One-third of patients have limb anomalies and many have short digits.  The facies is considered by some as characteristic with a square configuration, broad forehead, flat midface, and a broad nasal bridge.

Infant and childhood morbidity is high with feeding difficulties a major cause of death.

Genetics

Many cases occur sporadically but family patterns consistent with autosomal dominant inheritance are common as well.  Advanced paternal age may be a factor in de novo cases.  Sequence variants of multiple types have been reported in the CHD7 gene (8q12.1-q12.2) in more than 90% of familial patients.  The gene product is a DNA –binding protein that impacts transcription regulation via chromatin remodeling.

Kallmann syndrome (hypogonadotropic hypogonadism and anosmia) has been considered to be allelic to CHARGE syndrome but may be the same disorder since mutations in CHD7 are responsible and many patients have other features characteristic of the syndrome described here.

Several patients with classical features of the CHARGE syndrome and de novo mutations in the SEMA3E gene (7q21.11) have also been described.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is lesion dependent but focused on airway, feeding, and cardiac defects at least initially.  Regular ophthalmologic and audiologic evaluations are recommended beginning in infancy.  Evidence for hypogonadism should be evaluated if puberty is delayed.  Nutrition must be monitored especially in those with serious feeding problems.  Hearing devices, with speech, occupational, and education therapy may be required.

References
Article Title: 
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