Related Experiment Videos
Infantile hypophosphatasia: autosomal recessive transmission to two related sibships
C A Moore1, J C Ward, M L Rivas
1Boling Center for Developmental Disabilities, Department of Pediatrics, Memphis, TN 38105.
Insights
Infantile hypophosphatasia can be inherited as an autosomal recessive condition with variable expressivity. This study shows that severe genetic defects in hypophosphatasia are not always lethal, even in homozygous or compound heterozygous forms.
Area of Science:
- Genetics
- Biochemistry
- Pediatrics
Background:
- Hypophosphatasia is a rare heritable disorder affecting bone mineralization.
- It is caused by deficient activity of the tissue nonspecific alkaline phosphatase (TNSALP) isoenzyme.
- Inheritance patterns have been debated, with suggestions of autosomal recessive (AR) or autosomal dominant (AD) modes.
Observation:
- A study examined three patients from a black family with infantile hypophosphatasia.
- Two brothers died from the disorder, while a cousin presented with severe symptoms but had a milder course.
- Family history revealed consanguinity among grandparents, suggesting a potential genetic link.
Findings:
- The inheritance pattern in this family was consistent with autosomal recessive transmission.
- Fibroblast TNSALP activity was less than 1% of normal in all affected individuals.
- Genetic defects appeared identical in all three patients, with no complementation in heterokaryon analysis.
Implications:
- Infantile hypophosphatasia can exhibit variable expressivity, even with severe genetic defects.
- Homozygosity or compound heterozygosity for hypophosphatasia is not necessarily lethal.
- This challenges previous assumptions about the lethality of severe forms of the disorder.
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.