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Multigenerational case examples of hypophosphatasia: Challenges in genetic counseling and disease management.

ABSTRACT: Hypophosphatasia (HPP) is an inherited metabolic condition caused by pathogenic mutations in the ALPL gene. This leads to deficiency of tissue non-specific alkaline phosphatase (TNSALP), resulting in decreased mineralization of the bones and/or teeth and multi-systemic complications. Inheritance may be autosomal dominant or recessive, and the phenotypic spectrum, including age of onset, varies widely. We present four families demonstrating both modes of inheritance of HPP and phenotypic variability and discuss the resultant challenges in disease management, genetic counseling, and risk assessment. Failure to consider different modes of inheritance in a family with HPP may lead to an inaccurate risk assessment upon which medical and reproductive decisions may be made. We highlight the essential role of high-quality genetic counseling and meaningful biochemical and molecular testing strategies in the evaluation and management of families with HPP.

SUBMITTER: Huggins E

PROVIDER: S-EPMC7578550 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Multigenerational case examples of hypophosphatasia: Challenges in genetic counseling and disease management.

Huggins Erin E Ong Ricardo R Rockman-Greenberg Cheryl C Flueckinger Lauren Bailey LB Dahir Kathryn M KM Kishnani Priya S PS

Molecular genetics and metabolism reports 20201021

Hypophosphatasia (HPP) is an inherited metabolic condition caused by pathogenic mutations in the <i>ALPL</i> gene. This leads to deficiency of tissue non-specific alkaline phosphatase (TNSALP), resulting in decreased mineralization of the bones and/or teeth and multi-systemic complications. Inheritance may be autosomal dominant or recessive, and the phenotypic spectrum, including age of onset, varies widely. We present four families demonstrating both modes of inheritance of HPP and phenotypic v ...[more]

PMID: 33101980

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Project description:BackgroundThe Arab population in Israel is a minority ethnic group with its own distinct cultural subgroups. Minority populations are known to underutilize genetic tests and counseling services, thereby undermining the effectiveness of these services among such populations. However, the general and culture-specific reasons for this underutilization are not well defined. Moreover, Arab populations and their key cultural-religious subsets (Muslims, Christians, and Druze) do not reside exclusively in Israel, but are rather found as a minority group in many European and North American countries. Therefore, focusing on the Arab population in Israel allows for the examination of attitudes regarding genetic testing and counseling among this globally important ethnic minority population.MethodsWe used a qualitative research method, employing individual interviews with 18 women of childbearing age from three religious subgroups (i.e., Druze, Muslim, and Christian) who reside in the Acre district, along with focus group discussions with healthcare providers (HCPs; 9 nurses and 7 genetic counselors) working in the same geographical district.ResultsA general lack of knowledge regarding the goals and practice of genetic counseling resulting in negative preconceptions of genetic testing was identified amongst all counselees. Counselors' objective of respecting patient autonomy in decision-making, together with counselees' misunderstanding of genetic risk data, caused uncertainty, frustration, and distrust. In addition, certain interesting variations were found between the different religious subgroups regarding their attitudes to genetic counseling.ConclusionsThe study highlights the miscommunications between HCPs, particularly counselors from the majority ethno-cultural group, and counselees from a minority ethno-cultural group. The need for nuanced understanding of the complex perspectives of minority ethno-cultural groups is also emphasized. Such an understanding may enhance the effectiveness of genetic testing and counseling among the Arab minority group while also genuinely empowering the personal autonomy of counselees from this minority group in Israel and other countries.

Project description:ObjectiveHypophosphatasia (HPP) is a rare, commonly unrecognized hereditary mineralization defect with a dramatically poor prognosis in severe cases. This study is the first to examine the detailed clinical and laboratory characteristics of patients with HPP and healthy carriers in Turkey.MethodsThe study data were obtained retrospectively from the files of 10 healthy carriers and of 16 cases with HPP (12 children and 4 adults) who were followed in our center from 2012 to 2016.ResultsThe annual incidence of perinatal lethal hypophosphatasia (PLH) was estimated to be approximately 1 case per 435,517 live births,, which is the first report from Turkey. The clinical courses of the cases differed depending on the type of HPP. All of the seven cases (58.3% of all cases) with perinatal lethal form of HPP died. A need for respiratory support (p=0.001), a history of pyridoxine-dependent seizures (p=0.001), a low chest circumference measurement (p=0.017), younger age at diagnosis (p=0.029), a small head circumference at the time of presentation (p=0.042), a low arm span to height ratio (p=0.048), and a low serum alkaline phosphatase (ALP) level (p=0.042) seemed to be predicting factors for mortality. The mean height standard deviation score of the patients and those of the healthy carriers did not differ significantly (p=0.173). Different mutations were detected in nine of 14 cases (64.2%) in whom an ALPL gene mutation analysis could be performed, and five of these cases (35.7%) had novel mutations. The most common mutations were c746G>T (five alleles), c346G>A (three alleles), and c.140C>T (three alleles). In addition, the most frequently observed genotype in Turkish HPP cases was autosomal-dominant c.346G>A (p.A116T) mutations which were detected in three cases in two different families.ConclusionBecause of the respiratory problems, especially the lung hypoplasia, the clinical course is poor in cases with the perinatal lethal form of HPP. Some minor abnormalities such as mild short stature and osteopenia could be observed in asymptomatic heterozygote carriers. Laboratory findings were normal in these cases.

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Multigenerational case examples of hypophosphatasia: Challenges in genetic counseling and disease management.

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Multigenerational case examples of hypophosphatasia: Challenges in genetic counseling and disease management.

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