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What's the Diagnosis?

June, 2018

Visual Diagnosis

William Otto, MD

A baby boy is born via repeat Cesarean section at 39 weeks gestational age after an unremarkable pregnancy. Prenatal labs were normal, including negative group B streptococcal testing. He was noted to have poor tone at birth, and developed respiratory distress shortly thereafter. Positive-pressure ventilation was trialed, but he was eventually intubated due to continued distress. His physical exam is remarkable for a narrow thorax and slightly bowed limbs. A chest radiograph is obtained, with the findings shown in the image. His parents are Mennonite, and they report that he had an older brother who died of a similar condition. Their other children are healthy. 

Of the following, the clinical condition causing the patient’s symptoms is:

A. Early onset neonatal sepsis

B. Hypophosphatasia

C. Jeune syndrome

D. Total anomalous pulmonary venous return

Correct Answer: B

The patient has exam findings, imaging and family history consistent with hypophosphatasia. Hypophosphatasia is characterized by mutations in the gene ALPL, which codes for the enzyme alkaline phosphatase.1 Patients will have hypercalcemia and a severely depressed alkaline phosphatase level. This leads to defective mineralization of bone. You can see on the radiograph that the bones are profoundly demineralized, with shortened limbs. Early onset neonatal sepsis could present in this fashion, but would not have the exam and radiographic findings seen in this patient. Jeune syndrome, also known as asphyxiating thoracic dystrophy, is a rare genetic condition characterized by abnormal formation of the bones and cartilage. Patients with Jeune syndrome will have a narrow, bell-shaped thorax, but will have normal bone mineralization. Total anomalous pulmonary venous return is a congenital cardiac defect where the pulmonary venous drainage does not return to the left atrium. This usually results in cyanosis as opposed to frank respiratory distress.

Hypophosphatasia occurs along a spectrum of disease, ranging from fetal demise without any bony mineralization at the severe end, to mild disease presenting as pathologic fractures in adults. Six clinical forms of hypophosphatasia have been recognized:1

  • the severe perinatal form (as seen in this infant), with respiratory insufficiency and hypercalcemia

  • the benign perinatal form, with prenatal skeletal manifestations that morph into a more mild form of hypophosphatasia

  • infantile hypophosphatasia, characterized by the onset of rickets before age 6 months without compensatory elevation in serum alkaline phosphatase levels

  • childhood hypophosphatasia, a mild form of disease with manifestations ranging from low bone mineral density for age to rickets, as well as premature loss of primary teeth with intact roots

  • adult hypophosphatasia, with stress fractures of the lower extremities in middle age

  • odontohypophosphatasia, characterized by early loss of primary teeth and/or severe dental caries, but without skeletal manifestations.

Patients with neonatal and infantile forms almost always present with rickets. Patients can also present with intractable seizures, which resolve with administration of pyridoxine (vitamin B6).

Diagnosis is made via genetic testing, with affected individuals having mutations in ALPL. Most infantile forms are inherited in an autosomal recessive manner, but the more mild forms can be inherited in an autosomal recessive or autosomal dominant fashion. Hypophosphatasia should be suspected in patients with low alkaline phosphatase levels, especially if clinical features or a family history are present. Other laboratory values that may be indicative of hypophosphatasia include elevated urine phosphoethanolamine, or elevated serum levels of pyridoxal 5'-phosphate.

Initial management attempts to minimize disease-related complications through supportive care. This is a multidisciplinary process, which involves subspecialists in genetics, endocrinology, neurology, nephrology, and even psychology. Recently, the development of enzyme replacement with tissue-nonspecific alkaline phosphatase (Strensiq®, or asfotase alfa) therapy has helped to ameliorate the morbidity and mortality of the more severe phenotypes of hypophosphatasia. In the past, patients with severe perinatal or infantile hypophosphatasia progressed to death fairly soon after birth, usually due to respiratory insufficiency. A recent report compared infants treated with subcutaneous asfotase alfa injections with historical controls. Treated infants had improved mineralization of bones, leading to improved respiratory function and improved survival (95 percent vs. 42 percent at age 1 year; and 84 percent vs. 27 percent at age 5 years, respectively).2 Studies regarding outcomes of infants treated with enzyme replacement therapy are ongoing, as a new phenotype of “treated perinatal and infantile HPP” emerges.


1 Hypophosphatasia. Mornet E, Nunes ME. 2007 [Updated 2016]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from:
2 Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia. Whyte, M. P., Rockman-Greenberg, C., Ozono, K., et al. 2016. The Journal of Clinical Endocrinology and Metabolism, 101(1), 334–342.