Case Histories
Case History #1
Clinical Form --Infantile Hypophosphatasia -- diagnosed at 2 months of age by Dr. John Campbell Rathbun
In 1946, Dr. John Campbell Rathbun, then a fellow in pediatrics at The Hospital For Sick Children, Toronto, Canada, was referred a 3-week-old boy who seemed well at birth but then lost weight, developed epileptic seizures and when held, cried as though in pain. Radiographs showed severe osteopenia, fractures, and metaphysical irregularities, but serum calcium and inorganic phosphate levels were repeatedly normal or elevated, and serum alkaline phosphatase (ALP) activity was paradoxically low. Despite a variety of attempted treatments, including vitamin D supplementation, his patient died at 2 months of age shortly after a series of tonic seizures. Several tissues obtained at autopsy, including specimens of bones that revealed histopathologic changes consistent with rickets, also were deficient in ALP activity. Accordingly, in 1948 Rathbun reported this new "developmental anomaly" as "hypophosphatasia."
More than one-half of a century later, approximately 300 cases of this inborn error of metabolism have been reported. Rathbun's patient is an example of the infantile form of the disease with an incidence of approximately 1 per 100,000 live births and a lethal outcome in approximately 50% of such patients. In hypophosphatasia, defective skeletal mineralization seems to reflect endogenous accumulation of inorganic pyrophosphate (PPi), an inhibitor of skeletal mineralization. Epilepsy occurs in severely affected infants possibly because of disturbed vitamin B6 metabolism. There is no established medical treatment, but preliminary reports indicate that marrow cell transplantation rescued one severely affected girl and seemed to ameliorate the skeletal disease of tissue-nonspecific isoenzyme of ALP (TNSALP) knockout mice that recapitulate the infantile form of hypophosphatasia.
Despite a remarkable range of disease severity, all individuals with hypophosphataia studied to date have had a mutation(s) in he gene that encodes TNSALP ("liver/bone/kidney ALP"). No other gene or epigenetic factor has been implicated. Molecular studies have shown at least 65 distinctive deactivating TNSALP defects among hypophosphatasia patients worldwide.
In 1996, 50 years after the birth of her son, the mother of Rathbun's patient wrote to us to learn what was known about hypophosphatasia and to find out if carrier detection was possible for her family. The half-century of progress was reviewed, and a unique opportunity was recognized. After obtaining informed written consent, whole blood was obtained from her and her husband to extract leukocyte DNA for analysis of their TNSALP alleles. Denaturing gradient gel electrophoresis (DGGE) is established in our laboratory to investigate the molecular pathology of hypophosphatasia. Genomic DNA was isolated from lymphocytes using the Puregene kit (Gentra Systems, Inc. Minneapolis, MN, USA).
Although more than one-half of a century has elapsed since the death of Rathbun's patient, we believe that we have identified the TNSALP defects that caused this infant's death from hypophosphatasia. Rathbun's patient seems to have been a compound heterozygote for deactivating TNSALP missense mutations. In fact, all patients reported to date with either the perinatal or infantile form of hypophosphatasia are either homozygotes or compound heterozygotes for TNSALP defects. We know of no case of hypophosphatasia in which there has been uniparental disomy or evidence of involvement of another gene.
To date, our cumulative preliminary findings involving 20 probands agree with published reports that lethal hypophosphatasia is always inherited as an autosomal recesseive trait involving deactivating mutations in TNSALP. In Rathbun's patient, a different TNSALP mutation was discovered in each parent. Their son presumably inherited both defects and was a compound heterozygote with two defective TNSALP alleles.
Hypophosphatasia is now recognized to be an inborn error of metabolism featuring deficient activity of the tissue-nonspecific isoenzyme of ALP (TNSALP) caused by deactivating mutations in TNSALP.
excerpt (summary)
"Hypophosphatasia: Molecular Diagnosis of Rathbun's Original Case"
Bone Miner Res. 2001 Sep; 16 (9):1724-1727
Steven Mumm, 1,2; Jonathan Jones, 1; Patrick Finnegan, 1 and Michael P. Whyte, 1,2
1 Division of Bone and Mineral Diseases, Washington University School of Medicine at Barnes-Jewish Hospital Research Institute, St. Louis, Missouri, USA.
2 Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children, St. Louis, Missouri, USA.
Address reprint requests to:
Michael P. Whyte, M.D.
Shriners Hospitals for Children
2001 South Lindbergh Boulevard
St. Louis, MO 63131, USA
