Familial hypercholesterolaemia

Familial hypercholesterolaemia (FH), defined as the heritable occurrence of severe hypercholesterolaemia with cholesterol deposits in tendons and premature heart disease, is caused by at least four genes in sterol and lipoprotein pathways and displays varying gene-dose effects. The genes are the low-density lipoprotein (LDL) receptor, apolipoprotein (apo) B, proprotein convertase subtilisin/kexin 9, and the autosomal recessive hypercholesterolaemia (ARH) adaptor protein. All of these disorders have in common defective clearance of LDL within a complex system of lipid and lipoprotein metabolism and regulation. Normal cellular cholesterol and lipoprotein metabolism is reviewed before describing the disorders, their metabolic derangements and their clinical effects. FH is classified as two simplified phenotypes of disease according to the severity of the metabolic derangement. The dominantly inherited heterozygous phenotype comprises defects in the LDL receptor, apoB100, and neural apoptosis regulatory cleavage protein. The homozygous phenotype is co-dominant in defects of the LDL receptor, and occurs also as the ARH of adapter protein mutations. Defective binding of apoB100 does not result in a significant gene dose effect, but enhances the severity of heterozygotes for LDL receptor mutations. The genetic diagnosis of FH has provided greater accuracy in definition and detection of disease and exposes information about migration of populations. All of these disorders pose a high risk of atherosclerosis, especially in the homozygous phenotype. Studies of influences on the phenotype and responses to treatment are also discussed in the context of the metabolic derangements.     

Familial cylindromatosis

Familial cylindromatosis: we report a daughter with turban tumor and her mother with cylindromatosis. The dermal eccrine cylindroma arose as small, solitary lesions on the head of the mother when she was 28 years old. The following years other tumors became apparent. She was operated on several times. The first lesions appeared on the frontal part of the scalp of the daughter when she was 23 years old. Other tumors grew on the scalp. Histopathological examination of the excised tumors showed the same lesions in both the mother and the daughter: dermal eccrine cylindromata. Family history showed that the daughter's maternal aunt had a few tumors. Dermal eccrine cylindroma should be differentiated from malignant syndromes such as basal naevoid carcinoma or metastases and from neurofibromata. The gene of familial cylindromatosis was localised to chromosome 16q12-q13 and it was proposed that this gene is a tumor supressor gene.     

Familial dysautonomia

Familial dysautonomia is a developmental disorder of the sensory and autonomic nervous system. Recent studies have shown that two mutations in the gene IKBKAP are responsible for the disease. IKAP, the IKBKAP-encoded protein, is a member of the recently identified human Elongator complex. The major FD mutation is a splice mutation that results in aberrant tissue-specific mRNA splicing.     

Familial Hyperparathyroidism

Twenty-eight members of a family over three generations were studied; six of them had hyperparathyroidism. Four of the six were siblings and one of these had suffered from recurrent hyperparathyroidism. No member of the family showed any other significant endocrine disturbance or active peptic ulceration.Attention is drawn to the prominent lack of symptoms despite dangerous levels of hypercalcaemia and advanced disease with the consequent need for estimation of serum calcium levels in all close relatives. Multiple gland involvement is common in familial hyperparathyroidism and is often coupled with a tendency to recurrence, necessitating long-term follow-up. Histological appearances vary considerably, and the risk of recurrence is not limited to cases showing primary chief cell hyperplasia, with the implication that resection of three parathyroid glands and part of the remaining gland may be the treatment of choice in all cases of familial hyperparathyroidism when multiple gland involvement is found.     

Familial deletion

We report a retarded male with an unbalanced karyotype 45,XY,t(8;15) (p23;q12) showing small deletion of chromosome 8(p23 leads to pter) and 15(pter leads to q12). The same chromosome complement was also present in 4 normal family members over 3 generations.