Robert Rapaport, MD, Professor of Pediatric Endocrinology, and Director of the Comprehensive Growth Center at the Icahn School of Medicine, Mount Sinai Medical Center, New York City, discussed the differences between severe, primary IGF-1 deficiency and growth hormone (GH) deficiency in patients with short stature.

In young patients with short stature, GH deficiency is the most common cause. However, in a small subset of patients, the underlying problem is not GH deficiency but an abnormality in insulin-like growth factor-1 (IGF-1) levels. This peptide hormone was first discovered 50 years ago, and IGF-1 deficiency has been found to be caused by mutations in the GH receptor and defects in the IGF-1 gene. In patients with a specific subtype of severe, primary IGF-1 deficiency (SPIGF1D) called Laron syndrome, the specific cause is GH-receptor mutations.

Severe, primary IGF-1 deficiency is generally associated with the following patient characteristics: severe postnatal growth failure, short limb length, typical facial features (e.g., small forehead), and delays in sexual development and skeletal maturation. Crucially, affected children do not respond to a GH stimulation test.

Patients who have abnormally low GH levels can also be considered IGF-1 deficient. On the other hand, if the patient has normal GH levels, IGF-1 concentrations may still be abnormally low. According to Dr. Rapaport, patients with IGF-1 deficiency may be found to have abnormal IGF-1 levels across a spectrum from borderline low to extremely low, the latter of which represents the main feature of SPIGF1D (IGF-1 levels are 5–6 standard deviations below the mean for healthy individuals).

The only effective treatment for SPIGF1D is IGF-1 supplementation, with mecasermin, a human recombinant IGF-1 preparation. Although mecasermin is proven to increase patients’ growth velocity, patients taking the product are expected to attain “near normal” adult height only. It is given twice daily, and it does carry a risk of hypoglycemia, as IGF-1 lowers blood glucose levels. It is thus important that patients and their caregivers are well educated about avoiding this dangerous adverse effect.

CHAPTERS
Introduction 00:00
Primary IGF-1 Deficiency Overview 00:44
Severe IGF-1 Deficiency 3:32
Diagnosis in Children 4:42
Treatment for Severe IGF-1 Deficiency 5:29
Safety Considerations 8:07
Unmet Needs 8:56
Take Home Message 9:36

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Robert Rapaport, MD, Professor of Pediatric Endocrinology, and Director of the Comprehensive Growth Center at the Icahn School of Medicine, Mount Sinai Medical Center, New York City, discussed the differences between severe, primary IGF-1 deficiency and growth hormone (GH) deficiency in patients with short stature.

In young patients with short stature, GH deficiency is the most common cause. However, in a small subset of patients, the underlying problem is not GH deficiency but an abnormality in insulin-like growth factor-1 (IGF-1) levels. This peptide hormone was first discovered 50 years ago, and IGF-1 deficiency has been found to be caused by mutations in the GH receptor and defects in the IGF-1 gene. In patients with a specific subtype of severe, primary IGF-1 deficiency (SPIGF1D) called Laron syndrome, the specific cause is GH-receptor mutations.

Severe, primary IGF-1 deficiency is generally associated with the following patient characteristics: severe postnatal growth failure, short limb length, typical facial features (e.g., small forehead), and delays in sexual development and skeletal maturation. Crucially, affected children do not respond to a GH stimulation test.

Patients who have abnormally low GH levels can also be considered IGF-1 deficient. On the other hand, if the patient has normal GH levels, IGF-1 concentrations may still be abnormally low. According to Dr. Rapaport, patients with IGF-1 deficiency may be found to have abnormal IGF-1 levels across a spectrum from borderline low to extremely low, the latter of which represents the main feature of SPIGF1D (IGF-1 levels are 5–6 standard deviations below the mean for healthy individuals).

The only effective treatment for SPIGF1D is IGF-1 supplementation, with mecasermin, a human recombinant IGF-1 preparation. Although mecasermin is proven to increase patients’ growth velocity, patients taking the product are expected to attain “near normal” adult height only. It is given twice daily, and it does carry a risk of hypoglycemia, as IGF-1 lowers blood glucose levels. It is thus important that patients and their caregivers are well educated about avoiding this dangerous adverse effect.

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Robert Rapaport, MD, Professor of Pediatric Endocrinology, and Director of the Comprehensive Growth Center at the Icahn School of Medicine, Mount Sinai Medical Center, New York City, discussed the differences between severe, primary IGF-1 deficiency and growth hormone (GH) deficiency in patients with short stature.

In young patients with short stature, GH deficiency is the most common cause. However, in a small subset of patients, the underlying problem is not GH deficiency but an abnormality in insulin-like growth factor-1 (IGF-1) levels. This peptide hormone was first discovered 50 years ago, and IGF-1 deficiency has been found to be caused by mutations in the GH receptor and defects in the IGF-1 gene. In patients with a specific subtype of severe, primary IGF-1 deficiency (SPIGF1D) called Laron syndrome, the specific cause is GH-receptor mutations.

Severe, primary IGF-1 deficiency is generally associated with the following patient characteristics: severe postnatal growth failure, short limb length, typical facial features (e.g., small forehead), and delays in sexual development and skeletal maturation. Crucially, affected children do not respond to a GH stimulation test.

Patients who have abnormally low GH levels can also be considered IGF-1 deficient. On the other hand, if the patient has normal GH levels, IGF-1 concentrations may still be abnormally low. According to Dr. Rapaport, patients with IGF-1 deficiency may be found to have abnormal IGF-1 levels across a spectrum from borderline low to extremely low, the latter of which represents the main feature of SPIGF1D (IGF-1 levels are 5–6 standard deviations below the mean for healthy individuals).

The only effective treatment for SPIGF1D is IGF-1 supplementation, with mecasermin, a human recombinant IGF-1 preparation. Although mecasermin is proven to increase patients’ growth velocity, patients taking the product are expected to attain “near normal” adult height only. It is given twice daily, and it does carry a risk of hypoglycemia, as IGF-1 lowers blood glucose levels. It is thus important that patients and their caregivers are well educated about avoiding this dangerous adverse effect.

0 0

Robert Rapaport, MD, Professor of Pediatric Endocrinology, and Director of the Comprehensive Growth Center at the Icahn School of Medicine, Mount Sinai Medical Center, New York City, discussed the differences between severe, primary IGF-1 deficiency and growth hormone (GH) deficiency in patients with short stature.

In young patients with short stature, GH deficiency is the most common cause. However, in a small subset of patients, the underlying problem is not GH deficiency but an abnormality in insulin-like growth factor-1 (IGF-1) levels. This peptide hormone was first discovered 50 years ago, and IGF-1 deficiency has been found to be caused by mutations in the GH receptor and defects in the IGF-1 gene. In patients with a specific subtype of severe, primary IGF-1 deficiency (SPIGF1D) called Laron syndrome, the specific cause is GH-receptor mutations.

Severe, primary IGF-1 deficiency is generally associated with the following patient characteristics: severe postnatal growth failure, short limb length, typical facial features (e.g., small forehead), and delays in sexual development and skeletal maturation. Crucially, affected children do not respond to a GH stimulation test.

Patients who have abnormally low GH levels can also be considered IGF-1 deficient. On the other hand, if the patient has normal GH levels, IGF-1 concentrations may still be abnormally low. According to Dr. Rapaport, patients with IGF-1 deficiency may be found to have abnormal IGF-1 levels across a spectrum from borderline low to extremely low, the latter of which represents the main feature of SPIGF1D (IGF-1 levels are 5–6 standard deviations below the mean for healthy individuals).

The only effective treatment for SPIGF1D is IGF-1 supplementation, with mecasermin, a human recombinant IGF-1 preparation. Although mecasermin is proven to increase patients’ growth velocity, patients taking the product are expected to attain “near normal” adult height only. It is given twice daily, and it does carry a risk of hypoglycemia, as IGF-1 lowers blood glucose levels. It is thus important that patients and their caregivers are well educated about avoiding this dangerous adverse effect.

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Katie Gillick, Patient Advocate at Orsini Specialty Pharmacy, discusses the importance of patient and physician communication in the care of hypoparathyroidism.

Hypoparathyroidism is a rare endocrine disorder in which the parathyroid glands do not produce enough parathyroid hormone (PTH). Common signs and symptoms include cataracts, muscle cramps, tetany, pain in the face, legs, and feet, seizures, tingling sensation, and weakened tooth enamel.

Ms. Gillick’s journey began with thyroid cancer at age 23. After two surgeries to remove her thyroid, she began to experience symptoms of post-surgical hypoparathyroidism. Following her diagnosis, she was put on standard-of-care treatments which did not help control her symptoms. It was then that she decided to enroll in a phase 3 clinical trial of injectable parathyroid hormone. Ms. Gillick has now been on this medication for years with excellent management of her condition.

From both personal experience and patient survey results, Ms. Gillick describes brain fog as the biggest symptom burden of disease. This symptom affects nearly all aspects of daily life including relationships, ability to work, etc. However, because this symptom is hard to measure, it is not always properly addressed.

Ms. Gillick wishes that doctors knew that lab values do not always, and frequently do not, correspond with patients symptoms or lived experiences. It is therefore important for physicians to have good communication with their patients and not just brush things off when lab values look good.

Orsini Specialty Pharmacy dispenses over 70 different therapies for over 50 rare conditions, offering special handling and mail order options that retail pharmacies may not be able to offer, helping more patients get the medications they need.

For more information, visit https://www.hypopara.org/

To learn more about hypoparathyroidism and other rare endocrine disorders, visit https://checkrare.com/diseases/endocrine-disorders/

CHAPTERS
Introduction 00:00
Hypoparathyroidism Journey 00:16
What Physicians Should Know 2:13
Brain Fog and Symptom Burden 3:41
Speciality Pharmacies 5:12

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Maria Vogiatzi, MD, Division of Endocrinology at the Children's Hospital of Philadelphia, discusses the effect of Crenessity (crinecerfont) on bone age advancement in patients with congenital adrenal hyperplasia (CAH).

CAH refers to a group of genetic conditions that affect the adrenal gland production of hormones, particularly, the production of cortisol and androgen hormones. Persons with severe forms of the condition can be dramatically impacted. For example, females with a severe form of the condition may have ambiguous genitalia at birth and if not properly diagnosed, develop dehydration, poor feeding, diarrhea, vomiting and other health problems soon after. People with milder forms may not be diagnosed with the condition until adolescence or adulthood when they experience early signs of puberty or fertility problems. Excess androgens can also cause accelerated bone age maturation, leading to reduced adult height.

An abstract presented at ENDO 2026 aimed to describe changes in bone age advancement and predicted adult height in a subset of phase 3 CAHtalyst Pediatric (NCT04806451) participants. Crinecerfont is a first-in-class corticotropin-releasing factor type 1 receptor (CRF1) antagonist that is approved by the US Food and Drug Administration (FDA) as an adjunct to glucocorticoid replacement in patients 4 years of age and older with classic CAH.

A total of 103 participants were randomized and 41 had available assessments at baseline and month 24 of the study. Of these 41 participants, 63% had an advanced bone age at baseline. At month 24, 15% of these patients showed worsening bone age advancement, 31% showed no change, and 27% had improvements in bone age minus chronological age from 6 months up to 1 year. Additionally, 27% of participants had improvements in bone age minus chronological age of 1 year or more.

CHAPTERS
Introduction 00:00
CAH Overview 00:10
Treatment and Dosing Strategy 2:36
Growth Patterns in CAH 4:13
Effect of Crinecerfont on Bone Age Advancement 6:16
Crinecerfont Mechanism of Action 9:21

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Kristen Rohli, PhD, Associate Director of Research at Congenital Hyperinsulinism International, discusses congenital hyperinsulinism (HI) diagnosis and management.

Congenital HI is a condition caused by abnormally high levels of insulin, a hormone that helps control blood sugar levels. People with this condition have frequent episodes of low blood sugar (hypoglycemia). In infants and young children, these episodes are characterized by lethargy, irritability, or difficulty feeding. Repeated episodes of low blood sugar increase the risk for serious complications such as breathing difficulties, seizures, intellectual disability, vision loss, brain damage, and coma.

Early symptoms of congenital HI can be challenging to recognize because they often mimic normal behaviors in babies such as excessive crying and eating or generally feeling displeased or uncomfortable. Other, more severe symptoms such as seizures and blue skin, may prompt more tests to be run. These babies often present with high insulin and low glucose in lab tests. Ms. Rohli highlights that about 60% of patients are diagnosed within the first year of life.

The only FDA approved medication for congenital HI is diazoxide, a nondiuretic benzothiadiazine that primarily acts as an ATP-sensitive potassium channel opener. However, Ms. Rohli explains that around 50% of patients do not respond to this medication. Other medications, such as somatostatin analogs octreotide and lanreotide, are used off-label. There are also currently many investigational treatments going through the clinical trial pipeline.

Congenital Hyperinsulinism International provides support, research, and awareness for patients, caregivers, and families. Clinicians can access international guidelines for diagnosis and treatment and families can view a translation of those guidelines into lay terms and images. Additionally, the organization works to connect families with each other and with a global patient registry. Family conferences are held twice a year where patients and families can meet each other and connect with top researchers. The next conference will be held in Marseille, France in September 2026.

CHAPTERS
Introduction 00:00
Congenital HI Overview 00:12
Symptoms and Diagnosis 00:38
Current Management 2:48
Congenital Hyperinsulinism International 3:29

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Rachel Gafni, MD, Senior Research Physician at the National Institutes of Health, discusses results from the CALIBRATE clinical trial in patients with autosomal dominant hypocalcemia type 1 (ADH1).

ADH1 is a rare form of hypoparathyroidism caused by variants of the calcium‐sensing receptor gene (CASR). Inherited variants of CASR alter the set point for extracellular calcium, resulting in inadequate parathyroid hormone (PTH) secretion and inappropriate renal calcium excretion leading to hypocalcemia and hypercalciuria. The most common symptoms of ADH1 include muscle spasms in the hands and feet, muscle cramping, prickling or tingling sensations, and twitching of muscles.

CALIBRATE (NCT05680818) is a global, phase 3, randomized, controlled, open-label trial testing encaleret to treat patients with ADH1. Encaleret is an investigational, oral, negative allosteric modulator of the CASR.


All participants entered period 1, a 4-week standard of care maintenance period. Participants were then randomized to receive encaleret or continue standard of care in period 2, a 20 week dose titration period. Both treatment groups then entered period 3, a 4 week dose maintenance period, with the final follow-up at week 24. Standard of care treatment includes calcium and active vitamin D, which has been shown to worsen hypercalciuria, which may result in renal calcifications and/or chronic kidney disease.

A total of 67 patients with ADH1 due to 46 distinct CASR variants were randomized and 66 completed period 3. The composite primary endpoint assessed the proportion of those randomized to encaleret achieving target mean albumin-corrected blood calciumn (cCa) and 24-hour urine calcium excretion (UCa) at week 24 of period 3 compared to themselves when on standard of care at week 4 of period 1.

The endpoint was met in 75.6% of encaleret-treated participants at week 24 of period 3, compared to only 4.4% at period 1 week 4 of period 1. Encaleret increased mean cCa by day 3 and decreased mean UCa by week 3 during the dose escalation stage (period 2). These improvements were maintained throughout the study. Within the encaleret group, 91.1% had PTH greater than or equal to 15 pg/mL at week 24 of period 3 compared with only 6.7% at week 4 of period 1. Additionally, 91.1% achieved normal serum phosphate at week 24 compared with 55.6% at week 4.

Additional analyses showed that more participants randomized to encaleret (75.6%) had cCa and UCa within the target ranges by the end of the study compared to those randomized to standard of care (19%).

Encaleret was well-tolerated with no discontinuations in the encaleret arm. Few serious adverse events were reported with frequency similar between treatment arms.

CHAPTERS
Introduction 00:00
ADH1 Overview 00:27
Symptoms and Diagnosis 2:05
CALIBRATE Clinical Trial 8:49

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Melanie Gander, mother of a son with congenital adrenal hyperplasia (CAH), and Ambassador with Neurocrine Biosciences, discusses her son’s diagnostic journey with congenital adrenal hyperplasia (CAH).

CAH refers to a group of genetic conditions that affect the adrenal glands. Affected people lack an enzyme the adrenal glands need to make one or more of these hormones and often overproduce androgens. For example, females with a severe form of the condition may have ambiguous genitalia at birth and if not properly diagnosed, develop dehydration, poor feeding, diarrhea, vomiting and other health problems soon after. People with milder forms may not be diagnosed with the condition until adolescence or adulthood when they experience early signs of puberty or fertility problems.

Following the birth of her son, Ms. Gander explains that everything was normal. He was eating well and gaining weight as usual. It was not until their newborn follow-up appointment, where his newborn screening results showed slightly elevated markers for CAH, that there were any concerns. The family was then prompted to redo the newborn screening panel, where his levels came back significantly higher for CAH. However, he still showed no signs of disease.

Subsequent metabolic and electrolyte testing, including assessment of 17-hydroxyprogesterone (17-OHP) led to an official diagnosis of CAH, at which point he was started on treatment, even though he showed no signs or symptoms of the disease.

Her son, now 16 years of age, is taking hydrocortisone and following recommendations from the UK that dose 4 times per day following the circadian rhythm. He also takes fludrocortisone to retain sodium levels and started a new treatment a year ago that helps decrease androgen levels and allows for a lower dose of steroids.

Ms. Gander believes her son has a milder form, noting that they have been very lucky in terms of receiving a quick diagnosis and only experiencing a few crises where injection was necessary.

Ms. Gander stresses the importance of advocacy and better knowledge of CAH. There have been many instances where physicians don’t understand the burden of disease on the patient and caregiver, and where paramedics have not understood the disease and what to do in a crisis. She has worked to increase awareness through talks with EMS and implementing protocols for CAH.

CHAPTERS
Introduction 00:00
CAH Overview 00:14
Diagnostic Journey 00:47
Current Treatment 12:43
Importance of Education and Advocacy 15:21

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