pulmonary fibrosis

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
Article Title: 

Hermansky-Pudlak Syndrome

Clinical Characteristics
Ocular Features: 

Oculocutaneous hypopigmentation is common to all types of HPS.  The ocular manifestations are similar to that of other types of albinism.  Iris transillumination defects, nystagmus, and strabismus are common features.   Visual acuity is usually stable in the range of 20/40-20/300 and often accompanied by photophobia.  Foveal hypoplasia and fundus hypopigmentation are present similar to that found in other hypopigmentation disorders.  The same is true of excessive decussation of retinal neuron axons at the chiasm.  Many patients have significant refractive errors. 

Systemic Features: 

In addition to decreased hair, ocular, and skin pigmentation, HPS patients suffer from bleeding diathesis, platelet deficiencies, and accumulation of ceroid material in lysosomes.  Pigment can be found in large amounts in reticuloendothelial cells and in the walls of small blood vessels.  Some of the same features are found in Chediak-Higashi  syndrome (214500) which, however, has additional qualitative changes in leukocytes.   HPS2 differs from other forms of HPS in having immunodeficiency and congenital neutropenia.  Some patients, especially those with HPS1 and HPS4 mutations, have restrictive lung disease secondary to pulmonary fibrosis often causing symptoms in the third and fourth decades of life.  Others have granulomatous colitis, kidney failure, and cardiomyopathy.  Solar skin damage is a risk with actinic keratosis, nevi, lentigines and basal cell carcinoma seen in many patients.

Bleeding time is prolonged secondary to an impairment of the normal aggregation response of platelets.  Easy bruising, epistaxis, prolonged bleeding during menstruation, after tooth extraction, and after minor surgical procedures are often reported.  Platelets lack the normal number of 'dense bodies'.  Coagulation factor activity and platelet counts are normal.

The amount of hair and skin pigmentation is highly variable.  Some patients are so lightly pigmented that they are misdiagnosed as having tyrosinase-negative albinism while others have yellow to brown hair with irides blue to hazel.  Some darkening of hair is common. 

Genetics

This is an autosomal recessive genetically heterogeneous condition resulting from mutations in at least 12 loci: HPS1 (203300) at 10q23.1-q23.2, AP3B1 causing HPS2 (608233) at 5q14.1, and AP3D1 (617050) at 19p13.3 causing HPS 10, whereas in types HPS3 (606118) at 3q24, HPS4 (606682) at 22q11.2-q12.2, HPS5 (607521) at 11p15-p13, HPS6 (607522) at 10q24.32 the mutations themselves have not been characterized.  HPS7 is caused by mutations in the DTNBP1 gene (607145) located at locus 6p22.3 and HPS8 by mutations in the BLOC1S3 gene (609762) at 19q13.  The nature of the mutations is variable and often unique to the population in which they are found. 

Chediak-Higashi  syndrome (214500) is a somewhat similar disorder but with leukocyte abnormalities and results from a different gene mutation.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

It has been suggested that any patients with pigmentation disorders should be asked about bleeding problems to rule out HPS.  A hematologic consultation should be obtained if necessary, especially before elective surgery, to avoid bleeding complications through the use of appropriate preoperative measures.   Low vision aids can be helpful.  The skin should be protected from sunburn.  Lifelong surveillance is required for ocular and systemic problems.  The use of aspirin and indomethacin should be avoided. 

References
Article Title: 

Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome

Ammann S, Schulz A, Krageloh-Mann I, Dieckmann NM, Niethammer K, Fuchs S, Eckl KM, Plank R, Werner R, Altmuller J, Thiele H, Nurnberg P, Bank J, Strauss A, von Bernuth H, Zur Stadt U, Grieve S, Griffiths GM, Lehmberg K, Hennies HC, Ehl S. Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome. Blood. 2016 Feb 25;127(8):997-1006.

PubMed ID: 
26744459
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