Autosomal recessive hypophosphatasia manifesting in utero with long bone deformity but showing spontaneous postnatal improvement

Abstract

Context: Hypophosphatasia (HPP) is a heritable metabolic disorder of the skeleton that includes variable expressivity conditioned by gene dosage effect and the variety of mutations in the tissue nonspecific alkaline phosphatase (TNSALP) gene. Patient age when skeletal problems first manifest generally predicts the clinical course, with perinatal HPP causing bone disease in utero with postnatal lethality.

Objective: Our objective was to identify TNSALP mutations and characterize the inheritance pattern of a family with clinically variable HPP with one child manifesting in utero with long bone deformity but showing spontaneous prenatal and postnatal improvement.

Design: TNSALP enzyme and substrate analysis and TNSALP mutation analysis were performed on all family members.

Patients: A boy with HPP showing long bone deformity that spontaneously improved in utero and after birth is described. His older brother has the childhood form of HPP without findings until after infancy. His parents and twin sister are clinically unaffected.

Results: Both boys are compound heterozygotes for the same missense mutations in TNSALP, documenting autosomal recessive inheritance for their HPP. The parents each carry one defective allele.

Conclusions: The patient is an autosomal recessive case of HPP with prenatal long bone deformity but with spontaneous prenatal and postnatal improvement. Thus, prenatal detection by sonography of bowing of long bones from HPP, even with autosomal recessive inheritance, does not necessarily predict lethality but can represent variable expressivity or the effects of modifiers on the TNSALP defect(s).

Figure 1

Sonographic images of sib no. 1. A, Sharp mid-diaphyseal angulation of his right radius (white arrow) and ulna (black arrow) at 18-wk gestation. B, Sharp, mid-diaphyseal angulation (arrow) of his right humerus at 20-wk gestation. C, Improvement in angulation (arrow) of his right radius at 26-wk gestation. Calipers mark the ends of the radius. D, Mildly curved left femur at 34-wk gestation. Calipers mark the ends of the femur. E, Improvement over time of angulation of his right radius at 34-wk gestation. Calipers mark the ends of the radius.

Figure 2

A, Radiographic images of sib no. 1 at birth showing angulation of the right humerus, radius, and ulna, and mild bowing of the left femur. B, Inset of A detailing the angulation and callus formation of the right humerus (arrowhead).

Figure 3

Photographs of sib no. 1 at 17 months of age. A, Bowing of the right upper arm with posterior dimpling (arrow). B, Premature loss of teeth (loss of bottom two central incisors).

Figure 4

The older brother (sib no. 3). A, Frontal view showing premature loss of teeth at age 2.5 yr. B, Lateral view at age 2.5 yr showing macrocephaly, with a scaphocephalic contour. C, Radiograph at age 18 months showing radiolucencies (delineated by arrows) of the left proximal humerus projecting from the growth plate into the metaphysis.