Background

Welcome to the Part 1 of the 2022 HPP Case Discussion.

In October 2021- January 2022, insights on current perceptions and practice patterns were collected from specialists across Canada via a needs assessment questionnaire.

Key learning from the assessment:
  • There is acknowledgment that family mapping could accelerate new patient identification (69% agree)

Family Mapping could accelerate new patient diagnosis and help families better understand the inheritance of HPP among family members:
[1 being strongly disagree, 3 being neutral and 5 being strongly agree]

  • Less than half of responders have used family mapping and genetic testing to identify new patients (46%)
  • The most common reason responders provided for NOT utilizing this approach was reluctance from patients’ family members

Have you utilized family mapping and genetic testing interpretation to identify new patients?

See the Appendix for more data gathered from the assessment on testing and diagnosis!

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The intent of this 2-part series is to shed light on the education gaps identified through the assessment. Each issue will include a case study and provide additional information on best practices. This issue, Part 1, explores the benefits and challenges with implementing family mapping in Canadian HPP practice. Part 2 will focus on treatment best practices.

We are pleased to have Dr. Aliya Khan (McMaster University) leading this initiative, with support from Dr. Sarah Khan, MD FRPC (Bone Research and Education Clinic (BREC) and Credit Valley Hospital).

Introduction

HPP is a rare, life-threatening inherited disorder of bone and mineral metabolism. It affects approximately 1 per 100,000 births in Canada and is caused by loss of function mutations in the ALPL gene.¹ Mutations in this gene affect the tissue non-specific alkaline phosphatase (TNSALP) isozyme that is important for the mineralization of bones and teeth as well as the normal function of the neurologic, renal and musculoskeletal system.

HPP has a heterogeneous presentation with wide-ranging severity. There are six major clinical forms (by decreasing severity): perinatal, infantile, childhood (severe or mild), adult, and odontohypophosphatasia.

Common features and symptoms include²:

  • Persistently low ALP activity (exclude other causes of low alkaline phosphatase)
  • Reduced bone mineralization resulting in rickets in children and osteomalacia in adults
  • Fractures and skeletal abnormalities
  • Muscle Weakness
  • Respiratory failure in infants
  • Bone/joint/muscle pain
  • Developmental delays/impaired mobility
  • Chondrocalcinosis
  • Renal complications -nephrocalcinosis, hypercalciuria, nephrolithiasis
  • Dental complications including early loss of primary teeth
  • Neurologic complications – seizures, anxiety, restlessness, chronic pain
How is HPP diagnosed?

HPP is a clinical diagnosis made based on clinical features, laboratory findings and radiographic features. It can be confirmed with DNA analysis of the ALPL gene. A molecular diagnosis may not be present in all patients with HPP. A low alkaline phosphatase level should be further evaluated and other causes of a low alkaline phosphatase should be excluded.³ Elevation of the natural substrates of the alkaline phosphatase enzyme include elevated vitamin B6 levels, and if elevated also suggests the presence of HPP. Imaging includes renal ultrasound searching for nephrocalcinosis or nephrolithiasis as well as x-rays of the skeleton with evaluation of skeletal abnormalities as well as chondrocalcinosis.

What is family mapping and how is it used?

HPP can be inherited in an autosomal recessive or autosomal dominant manner. Family mapping is the process of identifying at-risk family members and can be helpful in identifying individuals who may have the disease and may transmit it to others. Molecular testing is of great value in confirming the diagnosis and can be offered to at risk individuals.

The following case study, and subsequent discussion explores benefits and common challenges with integrating family mapping in routine practice.

Case Study

ID: 35-year-old female with a history of recurrent fractures with minimal trauma

Medical History: Depression for several years

Medications: citalopram 20 mg

Allergies: No known drug allergies

Family History: Father had corrective surgery for his skull in infancy

History of Present Illness: Patient recently developed a cough from a respiratory infection and developed multiple rib fractures. Also had a fall from standing height at the age of 25 at which time she sustained bilateral femoral stress fractures.

Was a full-term baby with no respiratory difficulty at birth and had normal muscle tone. She had no known skeletal deformities and met all her developmental milestones. She does recall her mother mentioning that she had “dental issues” as a child. She was recently seen by a dentist who noted significant mobility in her teeth and radiographic evidence of periodontitis. She has not lost any adult teeth. She continues to have ongoing joint pains and generalized fatigue.

Initial investigations revealed a significantly low ALP at 15 (35-120 U/L). Calcium, phosphate, magnesium, PTH and Vit D levels were all within normal limits. She also had a normal CBC and liver enzymes. A 24-hour urine calcium level was also normal. A skeletal survey was done which did not show chondrocalcinosis or other skeletal abnormalities. Renal ultrasound did not show evidence of nephrocalcinosis or nephrolithiasis.

Given her low ALP, history of fractures and dental disease, the suspicion for hypophosphatasia was raised. She had further investigations and vitamin B6 levels were elevated consistent with hypophosphatasia.

Genetic testing was completed which confirmed a heterozygous mutation in the ALPL gene. Genetic testing was subsequently offered to her family members. Her father consented to testing and was found to have HPP as well. Her sister did not consent to genetic testing.

Discussion

When should HPP be suspected?

There is significant heterogeneity in the presentation of HPP due to the various forms of the disease (i.e. infantile versus adult onset of disease).

It is important to routinely evaluate alkaline phosphatase levels and if found to be low this should be investigated further. Individuals who have features of multisystem disease with skeletal, dental, renal or neurologic manifestations should be further evaluated. A low ALP level requires further assessment to exclude the possibility of HPP.

Why use family mapping?

HPP is associated with serious life-altering complications at all ages, and significant mortality especially in patients who manifest in utero or at birth. Early identification and appropriate management is essential.

Family mapping can accelerate the identification of new patients and can shorten the time to diagnosis. This can allow timely intervention before the development of significant disease burden.

Current Challenges

Currently challenges with implementing family mapping using genetic testing include fear and misconceptions around the process of genetic testing. Individuals may also be concerned regarding how a diagnosis may negatively affect them (i.e., impact insurance or employment, or the need to take treatment for a disease they do not necessarily have symptoms of). Individuals may also have limited confidence in the interpretation of the results, as well as access to the required testing.

Considerations/tips for approaching the discussion around family mapping with patients and their families:

  • Emphasize the benefits of testing not just for the individual but also other family members as well (i.e. their children)
  • Inform patients that treatment for HPP is now available and can significantly improve the quality of life

Considerations/tips how to access testing:

  • Patients with a known family history of HPP should discuss this with their healthcare provider to obtain a referral to a metabolic bone disease specialist who can arrange for genetic testing and treatment of disease should it be needed.
Additional Resources
  1. Hypophosphatasia : Canadian Update on Diagnosis and Management³
  2. Investigation of ALPL variant states and clinical outcomes: An analysis of adults and adolescents with hypophosphatasia treated with asfotase alfa

Concluding Remarks

Delays in the recognition and diagnosis of HPP are common. There is an ongoing need to improve understanding and recognition of systemic manifestations of HPP and increase use of family mapping. This is especially important given that enzyme replacement therapy is now available in Canada and use of supportive treatments for specific symptoms and complications can significantly improve health outcomes for individuals with HPP.

It is important to remind patients that knowledge is power, and that the benefits of identifying/confirming an HPP diagnosis significantly outweigh any potential negative effects.

Stay Tuned: Part 2 of the HPP Case Discussion series will continue with information on best practices for assessing disease burden and treatment.

Support for this case series is provided by Alexion, AstraZeneca Rare Disease.

Appendix: Needs Assessment Feedback – Diagnosis and Family Mapping

 

The HPP needs assessment survey developed in collaboration with Dr. Aliya Khan was distributed to Canadian specialists with an interest/focus in the category.

Responder Demographics

Type of Practice:

Specialty Breakdown:

Provinces represented:

  • British Columbia
  • Alberta
  • Manitoba
  • Ontario
  • Québec
  • Nova Scotia
Diagnosis and Family Mapping

Which of the following do you most associate with the diagnosis of HPP?:
[Responders selected all that apply]

Have you utilized family mapping and genetic testing interpretation to identify new patients?

If no, why?

  • Reluctance from patients’ family members for genetic testing (43%)
  • No clinical manifestations (29%)
  • Other (29%- no further explanation provided)
  • Access (14%)

To what extent do you agree with the following:
[1 being strongly disagree, 3 being neutral and 5 being strongly agree]

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¹ Vogt M, Girschick H, Schweitzer T, Benoit C, Holl-Wieden A, Seefried L, Jakob F, Hofmann C. Pediatric hypophosphatasia: lessons learned from a retrospective single-center chart review of 50 children. Orphanet J Rare Dis. 2020 Aug 18;15(1):212. doi: 10.1186/s13023-020-01500-x. PMID: 32811521; PMCID: PMC7436954.

² Seefried, L., Dahir, K., Petryk, A., Högler, W., Linglart, A., Martos-Moreno, G.Á., Ozono, K., Fang, S., Rockman-Greenberg, C. and Kishnani, P.S. (2020), Burden of Illness in Adults With Hypophosphatasia: Data From the Global Hypophosphatasia Patient Registry. J Bone Miner Res, 35: 2171-2178. https://doi.org/10.1002/jbmr.4130

³ Khan, Aliya & Josse, R. & Kannu, Peter & Villeneuve, J. & Paul, T. & van uum, Stan & Greenberg, C.R.. (2019). Hypophosphatasia: Canadian update on diagnosis and management. Osteoporosis International. 30. 10.1007/s00198-019-04921-y.

Kishnani PS, Del Angel G, Zhou S, Rush ET. Investigation of ALPL variant states and clinical outcomes: An analysis of adults and adolescents with hypophosphatasia treated with asfotase alfa. Mol Genet Metab. 2021 May;133(1):113-121. doi: 10.1016/j.ymgme.2021.03.011. Epub 2021 Mar 26. PMID: 33814268.

Support for this case series is provided by Alexion, AstraZeneca Rare Disease.