Infantile hypophosphatasia: Autosomal recessive transmission to two related sibships

Abstract

Hypophosphatasia, a rare heritable form of rickets/osteomalacia, is characterized by deficient activity of the tissue nonspecific (liver/bone/kidney) isoenzyme of alkaline phosphatase (ALP). Signs may be present prenatally or not until late adult life. Although the infantile form of hypophosphatasia has usually been categorized as an autosomal recessive (AR) disorder, several studies suggest that childhood cases are the consequence of either AR or autosomal dominant (AD) inheritance and adult cases are primarily AD. Eastman and Bixler (J Craniofac Genet Dev Biol 3:213-234, 1983) propose that all cases of hypophosphatasia may reflect AD inheritance with 85% penetrance and homozygous lethality. We report on 3 patients with hypophosphatasia in a black family, first manifested clinically during infancy, where the pattern of inheritance for each is consistent with AR transmission. Two were brothers who died from the disorder. The other patient, a cousin, presented with classic stigmata of hypophosphatasia during infancy, but is now age 5 1/2 years and has had a much milder clinical course. Although consanguinity is absent, the maternal grandmothers are sibs as are the maternal grandfathers and the paternal grandmothers. The family history is otherwise negative for skeletal or dental disease. Laboratory and radiographic results are consistent with heterozygosity in each parent. Fibroblast ALP activity is less than 1% normal in all 3 patients with no complementation observed in heterokaryon analysis. Accordingly, the genetic defects appear to be identical in all 3 patients. Our findings show that infantile hypophosphatasia may be inherited as an AR condition where there is variable expressivity and that homozygosity or compound heterozygosity, as may be the case in this family, is not necessarily lethal.

Mild autosomal dominant hypophosphatasia: In utero presentation in two families

“…Family and molecular studies show that perinatal and infantile forms are autosomal recessive disorders [Henthorn et al, 1992;Moore et al, 1990], as are some cases of the childhood and adult forms [Richie, 1964]. However, family and molecular studies also suggest that autosomal dominant inheritance occurs in some mildly affected kindreds [Pourfar et al, 1972;Whyte et al, 1978;.…”

Analysis of the periodontal microbiota in childhood-type hypophosphatasia

“…HP is inherited predominantly with an autosomal recessive trait (Greenberg et al, 1990;Henthorn et al, 1992;Moore et al, 1990;Orimo et al, 1994;Weiss et al, 1989;Whyte, 1995). Elevated concentrations of prostaglandin E2 (PgE2) and of substrates of TNSALP, including pyridoxal-5 0 -phosphate, inorganic pyrophosphate, and phosphoethanolamine, occur in serum, tissues and urine.…”

Skeletal mineralization defects in adult hypophosphatasia—a clinical and histological analysis

“…Hypophosphatasia is an inherited disorder primarily characterized by defective mineralization of bones and teeth, which is caused by inactivating mutations of the gene ALPL, encoding the tissue non-specific alkaline phosphatase [1][2][3][4][5][6][7][8][9]. Depending on the type of mutation and the mode of inheritance, the disease is highly variable in its clinical expression and can be classified into six major forms (perinatal lethal, prenatal benign, infantile, childhood, adult, and odontohypophosphatasia) [10].…”