Prenatal diagnosis of hypophosphatasia.

Abstract

Congenital hypophosphatasia is a lethal short-limb dwarfism characterized by underossification of the bony skeleton, low serum alkaline phosphatase, and high urine phosphoethanolamine. This lethal dwarfism represents the most severe form of hypophosphatasia,1-3 All cases of hypophosphatasia are autosomal recessive, but there is a wide variation in severity, even within the same family.1 Levels of alkaline phosphatase in the amniotic fluid are variable and cannot be reliably used to diagnose this condition. 4 The prenatal sonographic diagnosis of hypophosphatasia has been reported at least six times previously, 4 -9 but in these cases there was a history of other family members with hypophosphatasia and the diagnoses rested on nonspecific findings of underossification of the skull and of limb shortening. We will report a case of congenital hypophosphatasia that we were able to confidently diagnose sonographically without a family history of the condition. CASE REPORTThe patient was a 16-year-old white female, gravida 1, para 0, abortus Q who conceived from consanguineous union. Review of the family history showed no previous genetic abnormalities.A sonogram performed at 27 weeks by menstrual dates, demonstrated a fetus consistent with a biparietal diameter of 7.8 em (31.3 weeks), a head circumference of 28.4 em (313 weeks), and an abdominal circumference of 25.6 em (297 weeks). The femoral lengths were t7 em (14.5 weeks) and t9 ern (15.1 weeks); humeral lengths were 2.3 em (167 weeks) and t9 em (152 weeks); and ulnar length was t9 ern (16.1 weeks). The skull was underossified; underossification was also noted in the facial bones, ribs, and limb bones (Fig. lA). The metacar· pal bones (Fig 18), neural arches of the spine (Fig. 2), and some of the vertebral bodies (Fig. 3) were unossified. These findings were considered diagnostic for hypophosphatasia.On delivery at term, radiographs (Fig. 4) and a low serum alkaline phosphatase (5 UfL, normal range of 37 to 132 U/L) confirmed the ultrasound diagnosis of hypophosphatasia. DISCUSSIONThe sonographic diagnosis of congenital hypophosphatasia in this case was based on the combination of (1) general underossification of the bones of the fetus, (2) limb shortening, (3) lack of ossification of groups of vertebral bodies, (4) lack of ossification of the neural arches of the spine, and (5) lack of ossification of the hands. The last three of these findings have not to our knowledge been described sonographically before and are based on previous radiographic observations. 1 - 3.5· 10Other frequently described radiographic observations, such as large metaphyseal areas in long bones that are poorly ossified in a ragged manner. 1 -3 ·u are not a major feature in our case and the sonographic appearance of such lesions has not been established. In our case, the skull and ribs appeared better ossified sonographically Received March 21. 1989, from the Department of Diagnostic Ultrathan radiographically.sound, Loma

Early prenatal sonographic diagnosis of congenital hypophosphatasia

“…The degree of moderate to severe micromelia and diffuse hypomineralization in hypophosphatasia may resemble that of OI type II. However, in contrast to the thickened bones of OI type II, the long bones in hypophosphatasia tend to be thin or may be absent 4–7 , as in the case presented here. The sonographic findings of diffuse demineralization, short‐limb dwarfism, and thin bones in our case tend to suggest severe hypophosphatasia rather than achondrogenesis or OI.…”

“…A deficiency in alkaline phosphatase thus leads to the deficient generation of bone crystals. The major sonographic features of congenital hypophosphatasia are short‐limbed dwarfism and decreased bone echogenicity due to diffuse hypomineralization 4–7 .…”

“…An accurate prenatal differentiation between severe hypophosphatasia and other forms of skeletal dysplasia may be difficult. The major causes of short‐limbed dwarfism with hypomineralization of bones include hypophosphatasia, osteogenesis imperfecta (OI) type II, and achondrogenesis 4–7 . The sonographic features of most cases of achondrogenesis are absent ossification of the vertebral bodies and sacrum. The calvarium, however, is ossified, in contrast to the echolucent appearance of the skull in hypophosphatasia.…”

Infantile hypophosphatasia: Successful prenatal assessment by testing for tissue‐non‐specific alkaline phosphatase isoenzyme gene mutations

“…Prenatal diagnosis of hypophosphatasia has been directed at the most severe perinatal (lethal) form which manifests skeletal change in utero and leads to stillbirth or death early in infancy (Benzie et al, 1976;Hoar and Rudd, 1976;Rattenbury et al, 1976;Rudd et al, 1976;Blau et al, 1977Blau et al, , 1978Hosli and Rudd, 1978;Mulivor et al, 1978;Garber et al, 1979;Kousseff and Mulivor, 1981;Leroy et al, 1982;Hausser et al, 1984;Maxwell et al, 1985;Warren et al, 1985;Wladimiroff et al, 1985;DeLange and Rouse, 1990;Greenberg et al, 1990;vanDongen et al, 1990;Brock and Barron, 1991;Kishi et al, 1991;Kleinman el al., 1991;Muller et a l , 1991;Tennstedt et al, 1993;Sat0 et al, 1994). The infantile form is also a candidate for prenatal assessment because it often has devastating consequences.…”

“…Prenatal diagnosis of severe hypophosphatasia has been attempted using various conventional approaches. Radiological techniques have included fetal radiography (Hausser et al, 1984;Leroy et al, 1982) and ultrasonography (Garber et al, 1979;Kleinman et al, 1991;Rudd et al, 1976;vanDongen et al, 1990;Wladimiroff et al, 1985;DeLange and Rouse, 1990). ALP activity has been assayed in cultured amniocytes (Kousseff and Mulivor, 1981;Blau et al, 1977Blau et al, , 1978Hoar and Rudd, 1976;Rattenbury et al, 1976), fibroblasts (Hosli and Rudd, 1978), chorionic villus samples (Brock and Barron, 1991;Muller et al, 1991;Warren et al, 1985;Maxwell et al, 1985), and serum obtained by cordocentesis (Rudd et aZ., 1976).…”