HUT (Hutterite)

DGM (Dutch-German Mennonite)

Inheritance: autosomal recessive
Genes: ALPL

Perinatal lethal hypophosphatasia
Infantile hypophosphatasia

Abnormal teeth
Early shedding of teeth
Bone fragility
Bone pain
Infant death
Skull deformity


Clinical Characteristics

General description (for patients):  

This is a severe and often fatal disease of mineral metabolism.  A defective enzyme leads to imbalances of calcium and phosphate leading to tooth malformations and early loss of teeth, with skeletal changes sometimes resembling those of rickets, affecting long bones, ribs, vertebrae, and even the skull.  The onset in severe cases can occur in the uterus and is evident at birth.  Bones are fragile and easily broken.  Bone pain may be present.

Medical description: 

In this severe form of hypophosphatasia, onset can be diagnosed prenatally and severe signs are often present at birth.  Heterozygotes may have low serum alkaline phosphatase and early shedding of teeth.  In this, the infantile form, defective osteogenesis leads to craniostenosis, severe skeletal abnormalities, hypercalcemia, and bone fragility with death usually in the first year of life.  Considerable clinical and biochemical heterogeneity occurs and no diagnostic test of metabolism is consistently abnormal.  However, low levels of alkaline phosphatase are often found in liver, bone, and kidney.  Parents (heterozygotes) may also have low levels of alkaline phosphatase in the serum.


At least two clinically dissimilar forms of hypophosphatasia have been described, the severe infantile and usually lethal form described here, plus a relatively asymptomatic adult form (OMIM #146300), both presumably caused by mutations in the same gene (ALPL) on chromosome 1 (1p36.1-p34).  Inheritance is autosomal recessive in both forms although rare families with the adult form have an apparently dominant pattern.  It is a prevalent disease among Canadian Mennonites of Dutch-German background.  A c.1001G>A mutation is responsible for the disease in this group in which the phenotypic variability includes perinatal, infantile, juvenile, and adult forms.  The latter two forms can result from compound heterozygosity at this locus.  At least one Hutterite patient has been found with the c.1001G>A mutation.


No cure is available for the enzyme defect.


Uniformly poor in this infantile form with most dying within the first year of life.

Ancillary treatments and support:

Gentile handling and padding are important because of the bone fragility.  Bone pain may require analgesics.

Specialists and specialty centers:

Orthopedist, Pediatrician.


Orton, N.C., Innes, A.M., Chudley, A.E., and Bech-Hansen, N.T.:  Unique disease heritage of the Dutch-German Mennonite population.  Am. J. Med. Genet. 146A: 1072-1087, 2008. PubMed ID: 18348259

Greenberg, C.R., Taylor, C.L., Haworth, J.C., Seargeant, L.E., Philipps, S., Trigs-Raine, B., and Chodirker, B.N.:  A homoallelic Gly317> Asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia  in Canadian Mennonites.  Genomics 17: 215-217, 1993.  PubMed ID: 8406453


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