Clinical trial: Growth Hormone Treatment in Patients With Aggrecan (ACAN) Deficiency (NCT03288103)

Eligibility criteria:
Inclusion Criteria:

          1. ACAN Deficiency - Patients must be heterozygous for a mutation in the ACAN gene. A
             mutation will be defined as:

             a. A heterozygous deletion of the entire gene or of >1 complete exons of the gene b.
             Any truncating mutation including frameshift, nonsense, splice site mutations within 2
             bases of the exon/intron boundary, and start loss variants c. Any missense mutation
             which meets the following criteria: i. It is absent in the Exome Aggregation
             Consortium Database (exac.broadinstitute.org) ii. It is predicted to be damaging by
             BOTH Polyphen2 and Sorting Intolerant From Tolerant (SIFT) iii. It segregates with the
             short stature phenotype in the family or is a de novo mutation d. In-frame insertions
             or deletions of >1 amino acid e. In-frame insertions or deletions of 1 amino acid must
             meet the same criteria as missense mutations. For the prediction programs, Alanine
             will be substituted for the deleted amino acid.

             f. NOTE - Retrospective data does not show any correlation between the type of
             mutation and the severity of short stature. Therefore, all mutations meeting the above
             criteria will be included as a single group.

          2. Age - Greater than or equal to 3 years 0 days. There is no specific upper age limit,
             but the onset of puberty will make the patient ineligible.

          3. Pre-pubertal

               1. Male subjects must have a testicular volume <4 cc as determined on physical
                  examination by a pediatric endocrinologist at the time of the screening visit

               2. Female subjects must be Tanner 1 for breast development as determined on physical
                  examination by a pediatric endocrinologist at the time of the screening visit

          4. Bone Age - The bone age as determined by the Greulich and Pyle method must be equal to
             or greater than the chronological age. Bone ages will be determined at the screening
             visit by a single centralized radiologist.

          5. Insulin-like growth factor (IGF-I) level within normal range for age and sex.

          6. Ability to provide informed consent before any trial-related activities

          7. NOTE - There is no specific height standard deviation criteria for inclusion in this
             study.

        Exclusion Criteria:

          1. Prior treatment with any of the following therapies:

             A. Growth hormone B. Insulin-like Growth Factor (IGF-I) C. Gonadotropin releasing
             hormone (GnRH) analog D. Aromatase Inhibitor E. Oxandrolone

          2. History of any type of malignancy

          3. Growth plate fusion - Defined as a bone age via the Greulich and Pyle method of 13
             years in females and 15 years in males

          4. Chronic medical condition known to affect growth including but not limited to:

             A. Cystic fibrosis B. Diabetes C. Inflammatory Bowel Disease D. Celiac Disease E.
             Asthma requiring a daily inhaled steroid dose > 400 micrograms of inhaled budesonide
             per day or equivalent F. Taking daily oral glucocorticoids for any reason G. Note -
             attention deficit hyperactivity disorder (ADHD) treated with a stimulant and treated
             hypothyroidism with a normal thyroid stimulating hormone (TSH) will NOT exclude the
             subject from participating in the trial.

          5. (BMI) <5th percentile (CDC growth charts)

          6. Any clinically significant abnormality on screening laboratory tests as determined by
             the principal investigator.

          7. Known or suspected allergy to trial medication, excipients, or related products.

          8. Contraindications to study medications, worded specifically as stated in the product's
             prescribing information.

          9. The receipt of any investigational drug within 90 days prior to this trial.
No condition on gender to be admitted to the trial.
No healthy subjects accepted to join the trial.
Subject must be at least 3 Years old.


Patient description (medical language): A 3-year-old girl is brought to the clinic by her parents for assessment of her short stature. Physical examination reveals short limbs and a relatively large head. She has a flat nasal bridge and a small midface. The girl's father exhibits similar physical features; however, her mother looks normal. The genetic testing reveals an autosomal dominant point mutation in the fibroblast growth factor receptor 3 (FGFR3) gene consistent with achondroplasia in both father and the child. The girl has not received any treatment yet, and it is her first visit after immigration to the US. The other mental and developmental examinations are unremarkable.

Patient description (patient's own words): I just brought my little 3-year-old girl to the clinic to have her checked up by the doctor. I was worried sick because she was smaller than her classmates. The lovely doctor performed a physical exam and she told me that she has short limbs and a larger head. My girl also has a flat nasal bridge and a small midface. My baby just has the face of her father, unlike me! They performed some genetic testing on my child and my husband and found out that both my husband and her have a mutation of the FGFR3 gene, which led the doctor to diagnose them with dwarfism. My baby never received any treatment and it was our first visit to the doctor since we arrived in the US. The other tests regarding her mental and physical development were perfectly fine.

Does the patient match the trial criteria? 0