Carl J. Witkop

Sclerosteosis Nemogenetic and pathophysiologic analysis of an American kinship

We studied an American kinship with sclerosteosis, an autosomal-recessive disorder of bone remodeling and bone overgrowth of the calvaria, skull base, and tubular bones. Unlike osteopetrosis, which is attributed to abnormal immune and osteoclast function as well as bone resorption, sclcrosteosis appears to be primarily a disorder of osteoblast (bone formation) hyperactivity. Related to cranial vascular and neural foramina1 narrowing and reduced intracranial volume, affected patients with sclerosteosis demonstrate frequent seventh nerve palsy, progressive optic and cranial neuropathics, mixed hearing loss, brainstem compression, intracranial hypertension with increased elastance, and sudden, premature death. Management should involve early childhood identification of homozygotes, monitoring and aggressive treatment of intracranial hypertension, and extensive bone removal from skull, posterior fossa, and cervical spine.

Hermansky-Pudlak syndrome: Ophthalmic findings

Prospective ophthalmic evaluation was performed in 20 individuals with Hermansky-Pudlak syndrome, a type of oculocutaneous albinism with an associated deficiency of dense bodies in platelets. The extent of visual impairment and the possible relationship to the degree of hypopigmentation were studied. All patients showed nystagmus, visual acuity ranged from 20/60 to 20/400, and correction of refractive error provided a mild improvement in vision. Iris pigmentation varied in amount and did not correlate with the visual acuity measurement. Foveal hypoplasia was found in all patients, but variability in macular transparency and vascular architecture was noted. Visual-evoked potentials performed in 11 patients demonstrated excessive decussation of optic fibers. Recognition of this form of oculocutaneous albinism is important because of the associated pulmonary, gastrointestinal, renal, and cardiac manifestations of Hermansky-Pudlak syndrome.

Manifestations of genetic diseases in the human pulp

Abstract The number of hereditary disorders accompanied by changes in pulp tissue is relatively small. Many metabolic disorders, particularly those in which a product accumulates in tissue, probably involve changes in this organ. As pulp tissue is relatively easy to obtain from deciduous teeth and as many of these diseases commence in childhood, a pulpectomy technique might offer better methods of diagnosis. Further pulp tissue should offer an especially good source of material for cultures. Cultures have been used to detect heterozygotes of some of these conditions and to supply the material necessary for biochemical work, freeing the investigator from depending upon biopsies.

Hypoplastic enamel, onycholysis, and hypohidrosis inherited as an autosomal dominant trait: A review of ectodermal dysplasia syndromes

A syndrome consisting of a hypocalcified-hypoplastic enamel, onycholysis with subungual hyperkeratosis, seborrheic dermatitis of the scalp, and hypofunction of the sweat glands with rough dry skin is inherited as an autosomal dominant trait in a kindred of Caucasian ancestry.

Hermansky-Pudlak Syndrome in a Swiss Population

Tyrosinase-positive albinism, previously diagnosed as Hermansky-Pudlak Syndrome (HPS), has been examined in four generations from a village of the canton Valais, Switzerland. Homozygotes, obligate heterozygotes and putative heterozygotes in this geneology yielded lower than normal membrane-associated thioredoxin reductase (TR) activities compared with normal family members and controls. All of the homozygotes and 50% of each the obligate and putative heterozygotes showed an increase in bleeding time associated with storage-pool-deficient platelets lacking dense bodies. The TR activity profile and the platelet-dense body deficiency in the Swiss albinos was the same as that in the HPS population from Puerto Rico. However, in albinos from Puerto Rico, there is an accumulation of ceroid/lipofuscin-like pigment in lysosomal structures causing tissue damage, and, upon kidney involvement, this leads to increased urinary dolichol excretion. Approximately half of the Puerto Rican HPS cases had clinical evidence of storage disease with restrictive lung disease, granulomatous colitis, kidney failure and cardiomyopathy. By comparison, the Swiss HPS geneology had a normal life expectancy with no significant evidence for ceroid accumulation or urinary dolichol excretion. An examination of antioxidant enzymes, catalase, TR and glutathione reductase in epidermal suction blisters from Swiss HPS homozygotes showed a similar result for catalase and TR levels to the depigmented epidermis of patients with vitiligo, except that intracellular TR was found to be calcium free in HPS compared with vitiligo. Intracellular glutathione reductase levels were highest in HPS. Both the Swiss and Puerto Rican HPS homozygotes and heterozygotes have giant melanosomes in skin melanocytes.

Auditory System Abnormalities in Human Albinos

Auditory abnormalities were evaluated in human albinos using temporary threshold shift and dichotic listening tasks. Albinos exhibited a greater temporary threshold shift than did normally pigmented individuals after exposure to a fatiguing tone. In the dichotic listening task, albinos demonstrated a significantly larger right ear advantage than normally pigmented individuals. These results support earlier work indicating that hemispheric asymmetries are present in the albino auditory system and suggest that abnormalities may be present at the cochlear level as well.

Albinism in Nigeria with delineation of new recessive oculocutaneous type

Seventy‐nine Nigerian oculocutaneous albinos were investigated. Fifty‐six had typical tyrosinase‐positive albinism (TPA) and 23 had brown albinism (BA), a new oculocutaneous type. The TPA were characterized by localized but no generalized skin pigment, yellow hair, blue to brown irides, nystagmus, and reduced or absent retinal pigment. Localized skin pigment included freckles and lentigines. The iris and skin pigment were the result of the slow accumulation of pigment with age as both were found in older individuals. The most severe skin changes were premalignant keratoses and squamous cell carcinoma of the skin, and the skin malignancies were the major factor in limiting the lifespan for TPA. The BA were characterized by generalized light brown skin pigment, light brown hair, blue to brown irides, nystagmus, and reduced retinal pigment. There was little accumulation or change of pigment in the eyes or skin with age. The generalized light skin pigment was effective in reducing sensitivity to solar radiation and very few BA had premalignant keratoses. Pedigree analysis for BA suggested an autosomal recessive inheritance pattern.

Elevated urinary dolichol excretion in the hermansky-pudlak syndrome. Indicator of lysosomal dysfunction

The Hermansky-Pudlak syndrome, a triad of albinism, platelets lacking dense bodies, and storage of ceroid-like material in tissues, occurs approximately once in 2,000 northwestern Puerto Ricans. The manifestations of storage disease are variable and include granulomatous colitis, restrictive lung disease, kidney failure, and cardiomyopathy. The autofluorescent material stored in the Hermansky-Pudlak syndrome is histochemically similar to that stored in neuronal ceroid/lipofuscinosis. The material in neuronal ceroid/lipofuscinosis contains dolichols, which are components of lysosomes, and patients show increased urinary excretion of dolichols. This study of 49 patients with the Hermansky-Pudlak syndrome found that urinary dolichol levels are increased in those patients with evidence of ceroid storage in the kidneys but are not elevated when storage occurs in tissues other than the kidneys. The excretion of ceroid was not influenced by the saturation state of dietary fat. A defect in processing of membranes of lysosomes, melanosomes, and dense bodies may be involved in the syndrome.

Autosomal dominant hypodontia with nail dysgenesis: Report of twenty-nine cases in six families

Clinical details of twenty-three of twenty-nine cases of hypodontia and nail dysgenesis are presented. The classic features of severe hypodontia and a distinctive congenital nail defect were found in all families. The use of a simple method of sweat testing disclosed a minor deficiency of sweating in one family.

An electron optic analysis and explanation for the etiology of dentinal dysplasia

Abstract Metallurgically polished and fractured sections of teeth with dentinal dysplasia were prepared and studied under the scanning electron microscope. The morphologic data obtained suggested that the defect was one of the epithelial root sheath. A hypothetical model for the defect is presented and is supported both by scanning electron microscopy and classic histopathology.