abnormal dentition

Hypoparathyroidism, Familial Isolated

Clinical Characteristics
Ocular Features: 

Lens opacities may be present.

Systemic Features: 

The major signs and symptoms result from hypocalcemia. Neuromuscular irritability and various paresthesias may be present.  Some patients have  laryngeal spasm and latent tetany with grand mal seizures.  Alopecia, abnormal dentition and coarse brittle hair may be present.  Cognitive deficits and personality disorders are often a feature.  Brain imaging may show calcification of the basal ganglia.  Serum calcium levels are usually low while phosphorus levels are elevated.   Vitamin D precursor levels are usually low or low normal.

Genetics

Familial hypoparathyroidism may be due to mutations in the PTH gene (11p15.3) (either autosomal dominant or recessive inheritance) or in the GCMB gene (6p24.2) (autosomal dominant inheritance pattern).

There is also an X-linked form of hypoparathyroidism (307700) in which parathryroid tissue may be congenitally absent.

A family has been reported in which hypoparathryroidism was associated with lymphedema (247410) and progressive renal failure.  Ptosis, telecanthus, hypertrichosis, restrictive lung disease, and mitral valve prolapse may also be part of the disorder.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Normalization of calcium and phosphorus levels is a priority and this may result in some clearing of the lens opacities.  Cataract surgery may be indicated in selected individuals.

References
Article Title: 

Dyskeratosis Congenita

Clinical Characteristics
Ocular Features: 

The conjunctiva and eyelids are prominently involved as part of the generalized mucocutaneous disease.  Keratinization of the lid margins, absent lacrimal puncta, trichiasis, cicatrizing conjunctivitis, entropion, ectropion, blepharitis, sparse eyelashes, and symblephara are important features.  The cornea is also involved with keratinization of the epithelial surface and vascularization.  The nasolacrimal duct is sometimes blocked.  At least one patient has been reported to have an exudative retinopathy. 

Systemic Features: 

Dyskeratosis congenita consists of a heterogeneous (genetic and clinical) group of inherited bone marrow failure and premature aging syndromes with the common feature of shortened telomeres.  There is considerable variability in the clinical features.  Prominent manifestations include nail dysplasia, oral leukoplakia, abnormal dentition, and reticulated skin pigmentation. Some patients have cognitive impairments.  Liver failure, testicular atrophy, pulmonary fibrosis, aplastic anemia, and osteoporosis along with features of aging such as premature grey hair and loss are typical.  There is an increased risk of malignancies, especially acute myelogenous leukemia.  Bone marrow failure is the major cause of early death.

Genetics

At least three autosomal dominant, three autosomal recessive, and one X-linked form of dyskeratosis congenita are recognized.  Mutations in at least 7 genes have been implicated.

Autosomal dominant disease can result from mutations in the TERC gene (DKCA1; 3q36.2; 127550), the TERT gene (DKCA2; 5p15.33; 613989), and the TINF2 gene (DKCA3; 14q12; 613990).  Mutations in the TINF2 gene are also responsible for Revesz syndrome (268130) with many features of DKC in addition to ocular findings of an exudative retinopathy resembling Coats disease.

Autosomal recessive disease is caused by mutations in the NOP10 (NOLA3) gene (DCKB1; 224230; 15q14-q15), the  NHP2 (NOLA2) gene (DKCB2; 5q35; 613987), and the WRAP53 gene (DKCB3; 17p13; 613988).  Mutations in the TERT gene may also cause autosomal recessive disease known as DKCB4 (613989).  

The X-linked disease (DKCX) (Zinsser-Engman-Cole syndrome) results from a mutation in the DKC1 gene (Xq28; 305000).  The same gene is mutated in Hoyeraal-Hreidarsson syndrome (300240) which some consider to be a more severe variant of dyskeratosis congenita with the added features of immunodeficiency, microcephaly, growth and mental retardation, and cerebellar hypoplasia. 

The majority of mutations occur in genes that provide instructions for making proteins involved in maintainence of telemeres located at the ends of chromosomes.  Shortened telomeres can result from maintainence deficiencies although the molecular mechanism(s) remain elusive.

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

Treatment for DKC with hematopoietic stem cell transplantation can be curative but its long-term efficacy is poor.  Some advocate androgen therapy first.  Lifelong cancer surveillance and frequent ocular and dental evaluations are important with specific treatment as indicated.

References
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