Patient case (clinical description): 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's own account: 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.

Clinical trial: A Phase 2 Study of BMN 111 to Evaluate Safety, Tolerability, and Efficacy in Children With Achondroplasia

Eligibility criteria:
Inclusion Criteria:

          -  Parent(s) or guardian(s) are willing and able to provide written, signed informed
             consent

          -  5 to 14 years old at end of study

          -  ACH, documented by clinical grounds, confirmed by genetic testing

          -  At least 6-month of pretreatment growth assessment in Study 111-901 before study
             entry, and one standing height at least 6 months prior to screening for 111-202

          -  Negative pregnancy test at the Screening Visit for females ≥ 10 years old or who have
             begun menses

          -  If sexually active, willing to use a highly effective method of contraception while
             participating in the study

          -  Ambulatory, able to stand without assistance

          -  Willing and able to perform all study procedures as physically possible

          -  Parents/caregivers willing to administer daily injections to the subjects

        Additional inclusion Criteria Optional, Open-label Extension Phase:

          -  Appropriate written informed consent

        Exclusion Criteria:

          -  Hypochondroplasia or short stature condition other than ACH

          -  Have any of the following:

               -  Hypothyroidism or hyperthyroidism

               -  Insulin-requiring diabetes mellitus

               -  Autoimmune inflammatory disease

               -  Inflammatory bowel disease

               -  Autonomic neuropathy

               -  Recent acute illness associated with volume dehydration not completely resolved
                  prior to the first dose of study drug

          -  Unstable condition requiring surgical intervention during the study

          -  Growth plates have fused

          -  Have a history of any of the following:

               -  Renal insufficiency, defined as creatinine > 2 mg/dl

               -  Anemia

               -  Baseline systolic BP < 75 mm Hg or recurrent symptomatic hypotension or recurrent
                  symptomatic hypotension, recurrent symptomatic orthostatic hypotension

               -  Cardiac or vascular disease, including the following:

                    -  Cardiac dysfunction (abnormal echocardiogram [ECHO] including left ventricle
                       [LV] mass) at Screening Visit

                    -  Hypertrophic cardiomyopathy

                    -  Pulmonary Hypertension

                    -  Congenital heart disease with ongoing cardiac dysfunction

                    -  Cerebrovascular disease

                    -  Aortic insufficiency

                    -  Clinically significant atrial or ventricular arrhythmias

          -  Have an ECG showing any of the following:

               -  Right or left atrial enlargement or ventricular hypertrophy

               -  PR (period of time from the beginning of atrial depolarization until the
                  beginning of ventricular depolarization) interval > 200 msec

               -  QRS (The Q, R, and S heart waves that are measured on an electrocardiogram)
                  interval > 110 msec

               -  Corrected QTc-F (Measure of the corrected time between the start of the Q wave
                  and end of the T wave in the heart's electrical cycle) > 450 msec

               -  Second- or third-degree atrioventricular block

          -  Documented Vitamin D deficiency

          -  Require any investigational agent prior to completion of study period

          -  Have received another investigational product or investigational medical device within
             30 days before the Screening visit

          -  Use of any other investigational product or investigational medical device for the
             treatment of ACH or short stature

          -  Current chronic therapy with antihypertensive medications, angiotensin-converting
             enzyme (ACE) inhibitors, angiotensin II receptor blockers, diuretics, beta-blockers,
             calcium-channel blockers, cardiac glycosides, systemic anticholinergic agents, any
             medication that may impair or enhance compensatory tachycardia, diuretics, or other
             drugs known to alter renal or tubular function

          -  Treatment with growth hormone, IGF-1 (Insulin-like growth factor), or anabolic
             steroids in the previous 6 months or long-term treatment (> 3 months) at any time

          -  Long-term treatment (> 1 month) with oral corticosteroids

          -  Concomitant medication that prolongs the QT/QTc-F interval within 14 days or 5
             half-lives, whichever is longer, before the Screening visit

          -  Pregnant or breastfeeding at the Screening Visit or planning to become pregnant (self
             or partner) at any time during the study

          -  Limb-lengthening or bone-related surgery < 18 months prior to study enrollment

          -  Had a fracture of the long bones or spine within 6 months prior to screening (except
             for fracture of digits or toes)

          -  AST (Aspartate Transaminase) or ALT (Alanine Transaminase) at least 3x upper limit of
             normal (ULN) or total bilirubin at least 2x ULN

          -  Evidence of severe sleep apnea requiring surgery or new initiation of CPAP (Continuous
             positive airway pressure).

          -  History of malignancy and chemotherapy/radiation or currently under work-up for
             suspected malignancy

          -  Known hypersensitivity to BMN 111 or its excipients

          -  Have a condition or circumstance that, in the view of the Investigator, places the
             subject at high risk for poor treatment compliance or for not completing the study

          -  Concurrent disease or condition that would interfere with study participation or
             safety

          -  Have abnormal findings on baseline clinical hip exam or imaging assessments that are
             determined to be clinically significant as determined by the PI.

          -  Have a history of hip surgery or severe hip dysplasia

          -  Have a history of clinically significant hip injury in the 30 days prior to screening.

          -  History of slipped capital femoral epiphysis or avascular necrosis of the femoral
             head.

          -  Are unable to lie flat when in prone position

        Additional Exclusion Criteria for Optional, Open-label Extension Phase:

          -  Use of restricted therapies during the initial 6 months of the study

          -  Permanently discontinued BMN 111 during the initial 6 months of the study
No condition on gender to be admitted to the trial.
No healthy subjects accepted to join the trial.
Subject must be at least 5 Years old.
Subject must be at most 14 Years

Eligibility (NLI label): Contradiction