Table of Contents
Table of Contents
Wolfram's or DIDMOAD syndrome (OMIM ) (diabetes insipidus, diabetes mellitus, optic atrophy, and nerve deafness). (autosomal recessive and associated with non-immune complete and selective beta cell destruction and severe and progressive neuronal loss. Onset of diabetes is often in infancy. This syndrome appears to be responsive to thiamine. There are no characteristic skin findings reported. Wolfram syndrome is a rare inherited disorder that leads to an array of symptoms, including diabetes mellitus and blindness. More important, the syndrome's victims usually suffer from severe nervous system abnormalities that can be accompanied by behavior problems, psychiatric hospitalizations and--in 25 percent of cases--suicide attempts. Linkage analysis indicates that the likely location of the Wolfram gene is the short arm of chromosome 4. Between one in 50,000 to 100,000 people in this country inherit Wolfram syndrome. Although the syndrome itself is rare, experts estimate that about 1 in 100--or as many as 2.5 million Americans--possess a single copy of the mutated gene. Because these individuals, as well as close relatives of people with Wolfram syndrome, experience higher-than-normal rates of psychiatric illness.
Maturity onset Diabetes of Youth (MODY) syndrome (OMIM ). Variants of this syndrome may be very common in American blacks and individuals from India. In some families inheritance is autosomal dominant. Chlorpropamide-alcohol flushing may be a marker for this form.
Hemochromatosis (OMIM ). This is associated with the development of diabetes, and the autosomal recessive gene causing hemochromatosis is located within the major histocompatibility complex and is associated with HLA antigens A3 and B14. Patients with this syndrome often have insulin resistance in association with other manifestations of iron overload (bronzing of the skin, hepatomegaly, and cirrhosis). Affected asymptomatic individuals can now be identified even prior to increased serum ferritin, since the one in four siblings HLA identical to a hemochromatotic sibling are almost always homozygous for the involved gene. The gene causing hemochromatosis is very common in the general population (almost 10%); thus, approximately 2.5% of offspring of a patient with hemochromatosis will develop hemochromatosis. The sequelae of iron overload are preventable with simple phlebotomy, and therefore it is important to screen all first degree relatives of patients with hemochromatosis for abnormal iron metabolism (e.g., transferrin saturation, ferritin levels).
In secondary forms of iron overload including transfusional hemosiderosis, alcoholic cirrhosis, thalassemia, sideroblastic anemia, and porphyria cutanea tarda (OMIM ), iron accumulates in the reticuloendothelial system initially, but with increasing amounts of total body iron, excessive iron deposits eventually accumulate in parenchymal cells throughout the body producing a picture indistinguishable from hereditary hemochromatosis. Subnormal activity of hepatic uroporphyrinogen decarboxylase is responsible for the derangement of porphyrin biosynthesis in both sporadic and familial porphyria cutanea tarda, but the enzymatic defect is not clinically expressed in the absence of hepatic siderosis Pedigree studies support the hypothesis that HLA-linked hemochromatosis alleles are far more common inpatients with sporadic porphyria cutanea tarda than in individuals in the general population and may be responsible for the hepatic siderosis associated with most cases of sporadic porphyria cutanea tarda.
In a study of the skin manifestations of idiopathic hemochromatosis in 100 cases, there was a high frequency of ichthyosis-like states and koilonychia. In 50 cases with treated and non-treated groups, histological siderosis and clinical skin pigmentation were found to decrease post-phlebotomy whereas melanosis did not. Siderosis of eccrine sweat glands provided a probable diagnosis of the disease. Necrobiosis lipoidica and a black keratinous cyst have also been reported.
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophies an autosomal recessive disease characterized by a variable combination of (1) failure of the parathyroid glands, adrenal cortex, gonads, pancreatic beta cells, gastric parietal cells, and thyroid gland, and hepatitis; (2) chronic mucocutaneous candidiasis; and (3) dystrophy of dental enamel, nail pitting, alopecia areata, vitiligo and ocular keratopathy. This disease has many names, one being autoimmune polyglandular disease Type I.
In a recent study of 68 patients form 54 families, the clinical manifestations varied greatly and included from one to eight disease components, 63 percent of the patients having three to five of them. The initial manifestation was oral candidiasis in 41 patient(60%). The earliest endocrine component appeared at 19 months to 35 years of age. Eight patients (12%) had insulin-dependent diabetes mellitus, with the age at onset ranging from 4.1 to 37 years. Nine patients had vitamin B12 deficiencies that began at the ages of 6.1 to 47. Two female patients had non-goitrous hypothyroidism; no other patient had any thyroid autoimmune disease.
All 68 patients had oral candidiasis at least periodically; this condition first appeared at ages ranging from one month to 21 years. In six patients the candidiasis was very mild and disappeared spontaneously for as long as several years, but it always recurred. Other patients had chronic hypertrophic lesions, atrophic lesions, or both. Ungual candidiasis was present in 48 patients, and dermal candidiasis in six. The lesions were usually located on the hands and face. Four patients had esophagitis that was diagnosed by endoscopy, with stricture in one. Eleven other patients reported periods of retrosternal pain that resolved within days after the initiation of oral antifungal therapy. Ketoconazole 200 mg PO daily was effective in a double-blind trial; all six ketoconazole-treated patients showed clear clinical and mycological improvement, of oral and nail involvement. Death due to metastatic squamous cell carcinoma of the oral mucosa has been reported.
77% of patients had hypoplasia of the dental enamel that had begun at birth or during the first seven years. 2% had pitted dystrophy of the nails. The pits were 0.5 to 1 mm in diameter and affected several nails; The surface of the nail was otherwise smooth.