Hereditary Endocrine Syndromes

Endocrinologists and Geneticists Collaborate to Treat Hereditary Endocrine Syndromes

The Endocrine Genetics Program, within the Division of Endocrinology, Diabetes and Hypertension at Brigham and Women’s Hospital, sees approximately 120 patients a year with a range of genetic syndromes that display endocrine features.

This highly specialized program provides diagnostic evaluations and management of hereditary endocrine conditions for patients and their family members. The endocrinologist and genetic counselor team employs genetic tests, such as karyotype/microarray, single gene sequencing, gene panels, whole exome and whole genome sequencing, among others.

Specialists in the Program evaluate patients with the rare and sometimes fatal metabolic bone disease, hypophosphatasia, in addition to multiple endocrine neoplasia (MEN) syndromes, familial isolated pituitary adenomas (FIPA), Cowden syndrome, Albright hereditary osteodystrophy, maturity onset diabetes of the young (MODY), congenital adrenal hyperplasia, pheochromocytoma and paraganglioma predisposition syndromes, and many others.

“We are one of the few programs in the country to have this level of integration of a genetics program within an endocrine division,” said Dr. Barlev-Ehrenberg. “With some exceptions, endocrinologists do not routinely think about hereditary syndromes in their evaluations. One of our goals has been providing both formal and informal consultations and trainings to our endocrine faculty, which has greatly increased awareness of indications for referral.”

Genetic Testing for Hypophosphatasia

The presentation of hypophosphatasia can be highly variable, family members may have had subtle symptoms for years. “We will invite patients and their family members into the clinic for a comprehensive evaluation. We discuss hypophosphatasia, run clinical and genetic tests, counsel the family on the process of genetic testing and interpretation of results, and help them manage the disease,” said Adi Barlev-Ehrenberg, MD, MS, Director of the Endocrine Genetics Program.

The Program currently sees multiple families with juvenile onset and adult onset hypophosphatasia, which has led the specialists to take a particular interest in understanding and managing this disease. She said, “We are learning just how broad the range of symptoms can be, and this is leading us towards an increase in diagnosis.”

The Program screens for hypophosphatasia by testing for low levels of alkaline phosphatase, as the syndrome is caused by mutations in the ALPL gene, which leads to insufficient alkaline phosphatase and the accumulation of substrates, including inorganic pyrophosphate, which inhibit formation of hydroxyapatite from inorganic phosphate and calcium.

These metabolic changes lead to varying degrees of rickets, which in severe form can include hypercalcemia, nephrocalcinosis, and respiratory failure due to abnormal rib formation. In adults, symptoms can manifest very differently, with atypical bone pain and fragility fractures. In 2015, the FDA approved asfotase alfa, an enzyme replacement therapy (ERT) for the treatment of patients with perinatal, infantile, and juvenile-onset hypophosphatasia. This has allowed the Program to offer targeted treatment to those who are more severely affected.

Diseases that Elude Diagnosis Advance to Research Phase

When clinical testing cannot confirm a diagnosis, Dr. Barlev-Ehrenberg involves Division of Genetics researchers. “The patient may have an undiscovered disorder, so we work with our research team to determine if the patient and family qualify for whole genome sequencing on a research basis,” she said.

The Endocrine Genetics Program also works closely with genetics investigators with the Undiagnosed Disease Network (UDN), an NIH-funded program with seven clinical sites nationwide, including the consortium of Brigham and Women’s Hospital (BWH), Massachusetts General Hospital (MGH), and Boston Children’s Hospital (BCH). Experts at these hospitals evaluate and treat patients who suffer from diseases and symptoms that have eluded diagnosis.

Within the UDN, a patient will consult with a team that provides comprehensive clinical evaluation, cutting-edge genetic and genomic analysis, environmental exposure analysis, proteomics, metabolomics, systems biology and network medicine analysis.

“Genetics is constantly developing and our knowledge is rapidly expanding, but a great deal of genetic testing is already clinically available. Applying a collaborative approach allows us to both optimize clinical care and promote advances in research,” said Dr. Barlev-Ehrenberg.

Access to our Endocrinology Services

Our Physician Liaison Ellen Steward can provide direct assistance with patient referrals and consultations. Ellen can be reached at (617) 582-4733 or

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