Background/Patient description
Starting at four months of age, Patient J was referred to our Division of Gastroenterology, Hepatology and Nutrition for poor weight gain and malnutrition. Though linear growth was preserved, she struggled to gain weight. At age 16 months, her pediatrician astutely noted that Patient J had right-sided exotropia and was referred for ophthalmology evaluation. Our Division of Ophthalmology also noted nystagmus and decreased unilateral vision. Due to concerns for hypoplastic optic nerves, she had optic nerve and pituitary imaging requested.
Diagnostic findings
Around the same time, due to persistent slow weight gain, she was referred to our Division of Endocrinology and Diabetes. Her growth chart showed linear growth in the 10-25th percentile for age, but weight was still below fifth percentile for age despite nutritional intervention. She had no hypoglycemia and developmentally was meeting milestones. Pituitary imaging was completed right before our visit and showed optic nerve hypoplasia, ectopic pituitary gland, and absence of the pituitary infundibulum with a small adenohypophysis, a constellation known as septo-optic dysplasia (SOD). Because this condition can be associated with variable pituitary deficiencies, it is important to assess pituitary function (growth hormone, thyroid stimulating hormone, cortisol, arginine vasopressin deficiency) regularly in these individuals. Growth hormone deficiency is the most common condition associated with SOD. While some may manifest signs of severe hormone deficiencies early in life, depending on the severity of the dysplasia, some may have normal pituitary function that declines over time.
An endocrine evaluation of Patient J’s pituitary function showed normal cortisol but low thyroxine measurements with TSH levels within the reference range. This constellation of labs in the setting of SOD is consistent with central hypothyroidism, easily treated with levothyroxine. In this case, lab testing of free T4 levels will be the best indicator of adequate thyroid replacement, since the TSH response is not reliable in pituitary deficiencies.
Clinical course/treatment
Patient J responded well to levothyroxine and had no episodes of hypoglycemia. She continued to have stable cortisol levels, so we simply monitored, though she later developed borderline cortisol function, so we started her on stress dose steroids for moderate to severe illness, infection and fever, and for procedures requiring anesthesia or surgery. Growth progressed as expected, and she had no hypoglycemia despite modestly low IGF-1 levels, so we held off on GH therapy initially. Her parents were aware that this was likely to change in the future.
She remained stable on levothyroxine and cortisol, but by age three, she began to have slower linear growth despite better weight gain. Her 8am cortisol level was again low, so we pursued growth hormone and ACTH stimulation testing. These tests showed she had near undetectable stimulated GH levels (peak GH 0.69 ng/ml, normal 10 or higher) and persistently low cortisol levels as well. We started her on growth hormone replacement as well as full physiologic cortisol replacement. Almost immediately, her linear growth was restored. Over time, we have adjusted her growth hormone dose for weight, and she continues to grow well. She has remained on levothyroxine and hydrocortisone as well.
Outcomes
Patient J is now 12 years old. In the last two years, we have been watching closely for pubertal development, though there is a family history of delayed puberty. She did not have spontaneous breast maturation, so we began to monitor gonadotropins: age 11 years, 3 months LH was 0.005 mIU/ml, estradiol <2.5 g/ml, age 11y6m LH 0.012 mIU/ml, estradiol <2.5 pg/ml, and age 12 y6m LH 0.005 mIU/ml and estradiol <2.5 pg/ml. This lack of gonadotropin rise at an expected age of puberty in the setting of multiple pituitary hormone deficits most likely is due to hypogonadotropic hypogonadism (HH). Estrogen is critical for optimal bone accrual. Because evidence shows that delayed treatment of HH can negatively impact bone health, we started Patient J on estradiol replacement therapy at age 12 years, 6 months. For purposes of pubertal induction, transdermal 17-B estradiol therapy is used due to its beneficial safety profile, its similarity to physiologic estrogen, and ease of delivering very low doses. We use a stepwise dose escalation over a two-year period to mimic as closely as possible the typical effects that occur in adolescent females. We expect to see onset of breast buds with initiation of estradiol and subsequent maturation with menarche occurring after about 18-24 months of estrogen exposure, similar to the natural progression of puberty in many females. We also expect she will have a growth spurt as all females do when puberty starts, driven by estrogen exposure.
Her dynamic personality has withstood multiple oral medications, daily GH injections and now transdermal estradiol. She is growing up to a be a very mature young lady and wants to be in the healthcare field when she grows up, to “help the other kids just like me!”
Discussion
Random GH levels are not reliable since GH is secreted in a pulsatile fashion during stages of sleep. IGF-1 and IGF-BP3 are downstream signals of GH production that are a more reliable reflection of GH secretion in most patients. Linear growth in infants and toddlers with pituitary defects may be variable depending on severity of GHD. Severe GHD in infants and toddlers typically causes hypoglycemia, microphallus in males, frontal bossing and a cherubic phenotype, with variable slow linear growth. Untreated GHD may lead to growth failure, deficits in body composition, including disproportionate lean body muscle mass and fat mass, dyslipidemia and even abnormal bone density. Patients who have mild or moderate GHD may have fewer manifestations, and in fact, may even grow normally in the first few years of life, but may eventually demonstrate growth failure with deficits in body composition. Treatment with growth hormone (somatropin) leads to improved linear growth that matches genetic potential, improvement of hypoglycemia if relevant, and restoration of normal body composition.
While GH treatment is important, it is not without potential side effects: headaches and growing pains at a minimum, while severe adverse effects may include pseudotumor cerebri or slipped capital femoral epiphyses. Because adverse effects may be severe, it is important to be thoughtful when starting growth hormone therapy, and we carefully counsel families about side effects. In infants and toddlers with hypoglycemia, doses will be titrated to keep BG normal. In children without hypoglycemia and normal growth, and/or normal IGF1, it is plausible to hold off on GH therapy until a need for treatment is demonstrated. In our patient, because she did not have hypoglycemia and linear growth was normal early on, we opted to hold off on GH therapy until early childhood.
Key points
- Patient J presented in infancy with poor weight gain and was later diagnosed with septo-optic dysplasia (SOD) after imaging revealed optic nerve hypoplasia and pituitary abnormalities.
- Developed central hypothyroidism, growth hormone deficiency, ACTH deficiency, and hypogonadotropic hypogonadism over time.
- Successfully managed with levothyroxine, hydrocortisone, growth hormone and estradiol therapy.
- Illustrates the progressive, evolving nature of pituitary deficiencies in SOD and the importance of ongoing endocrine surveillance and multidisciplinary care.
- Patient now thriving at age 12, demonstrating resilience and strong engagement in her care.
Featured in this article
Experts
Specialties & Programs
Background/Patient description
Starting at four months of age, Patient J was referred to our Division of Gastroenterology, Hepatology and Nutrition for poor weight gain and malnutrition. Though linear growth was preserved, she struggled to gain weight. At age 16 months, her pediatrician astutely noted that Patient J had right-sided exotropia and was referred for ophthalmology evaluation. Our Division of Ophthalmology also noted nystagmus and decreased unilateral vision. Due to concerns for hypoplastic optic nerves, she had optic nerve and pituitary imaging requested.
Diagnostic findings
Around the same time, due to persistent slow weight gain, she was referred to our Division of Endocrinology and Diabetes. Her growth chart showed linear growth in the 10-25th percentile for age, but weight was still below fifth percentile for age despite nutritional intervention. She had no hypoglycemia and developmentally was meeting milestones. Pituitary imaging was completed right before our visit and showed optic nerve hypoplasia, ectopic pituitary gland, and absence of the pituitary infundibulum with a small adenohypophysis, a constellation known as septo-optic dysplasia (SOD). Because this condition can be associated with variable pituitary deficiencies, it is important to assess pituitary function (growth hormone, thyroid stimulating hormone, cortisol, arginine vasopressin deficiency) regularly in these individuals. Growth hormone deficiency is the most common condition associated with SOD. While some may manifest signs of severe hormone deficiencies early in life, depending on the severity of the dysplasia, some may have normal pituitary function that declines over time.
An endocrine evaluation of Patient J’s pituitary function showed normal cortisol but low thyroxine measurements with TSH levels within the reference range. This constellation of labs in the setting of SOD is consistent with central hypothyroidism, easily treated with levothyroxine. In this case, lab testing of free T4 levels will be the best indicator of adequate thyroid replacement, since the TSH response is not reliable in pituitary deficiencies.
Clinical course/treatment
Patient J responded well to levothyroxine and had no episodes of hypoglycemia. She continued to have stable cortisol levels, so we simply monitored, though she later developed borderline cortisol function, so we started her on stress dose steroids for moderate to severe illness, infection and fever, and for procedures requiring anesthesia or surgery. Growth progressed as expected, and she had no hypoglycemia despite modestly low IGF-1 levels, so we held off on GH therapy initially. Her parents were aware that this was likely to change in the future.
She remained stable on levothyroxine and cortisol, but by age three, she began to have slower linear growth despite better weight gain. Her 8am cortisol level was again low, so we pursued growth hormone and ACTH stimulation testing. These tests showed she had near undetectable stimulated GH levels (peak GH 0.69 ng/ml, normal 10 or higher) and persistently low cortisol levels as well. We started her on growth hormone replacement as well as full physiologic cortisol replacement. Almost immediately, her linear growth was restored. Over time, we have adjusted her growth hormone dose for weight, and she continues to grow well. She has remained on levothyroxine and hydrocortisone as well.
Outcomes
Patient J is now 12 years old. In the last two years, we have been watching closely for pubertal development, though there is a family history of delayed puberty. She did not have spontaneous breast maturation, so we began to monitor gonadotropins: age 11 years, 3 months LH was 0.005 mIU/ml, estradiol <2.5 g/ml, age 11y6m LH 0.012 mIU/ml, estradiol <2.5 pg/ml, and age 12 y6m LH 0.005 mIU/ml and estradiol <2.5 pg/ml. This lack of gonadotropin rise at an expected age of puberty in the setting of multiple pituitary hormone deficits most likely is due to hypogonadotropic hypogonadism (HH). Estrogen is critical for optimal bone accrual. Because evidence shows that delayed treatment of HH can negatively impact bone health, we started Patient J on estradiol replacement therapy at age 12 years, 6 months. For purposes of pubertal induction, transdermal 17-B estradiol therapy is used due to its beneficial safety profile, its similarity to physiologic estrogen, and ease of delivering very low doses. We use a stepwise dose escalation over a two-year period to mimic as closely as possible the typical effects that occur in adolescent females. We expect to see onset of breast buds with initiation of estradiol and subsequent maturation with menarche occurring after about 18-24 months of estrogen exposure, similar to the natural progression of puberty in many females. We also expect she will have a growth spurt as all females do when puberty starts, driven by estrogen exposure.
Her dynamic personality has withstood multiple oral medications, daily GH injections and now transdermal estradiol. She is growing up to a be a very mature young lady and wants to be in the healthcare field when she grows up, to “help the other kids just like me!”
Discussion
Random GH levels are not reliable since GH is secreted in a pulsatile fashion during stages of sleep. IGF-1 and IGF-BP3 are downstream signals of GH production that are a more reliable reflection of GH secretion in most patients. Linear growth in infants and toddlers with pituitary defects may be variable depending on severity of GHD. Severe GHD in infants and toddlers typically causes hypoglycemia, microphallus in males, frontal bossing and a cherubic phenotype, with variable slow linear growth. Untreated GHD may lead to growth failure, deficits in body composition, including disproportionate lean body muscle mass and fat mass, dyslipidemia and even abnormal bone density. Patients who have mild or moderate GHD may have fewer manifestations, and in fact, may even grow normally in the first few years of life, but may eventually demonstrate growth failure with deficits in body composition. Treatment with growth hormone (somatropin) leads to improved linear growth that matches genetic potential, improvement of hypoglycemia if relevant, and restoration of normal body composition.
While GH treatment is important, it is not without potential side effects: headaches and growing pains at a minimum, while severe adverse effects may include pseudotumor cerebri or slipped capital femoral epiphyses. Because adverse effects may be severe, it is important to be thoughtful when starting growth hormone therapy, and we carefully counsel families about side effects. In infants and toddlers with hypoglycemia, doses will be titrated to keep BG normal. In children without hypoglycemia and normal growth, and/or normal IGF1, it is plausible to hold off on GH therapy until a need for treatment is demonstrated. In our patient, because she did not have hypoglycemia and linear growth was normal early on, we opted to hold off on GH therapy until early childhood.
Key points
- Patient J presented in infancy with poor weight gain and was later diagnosed with septo-optic dysplasia (SOD) after imaging revealed optic nerve hypoplasia and pituitary abnormalities.
- Developed central hypothyroidism, growth hormone deficiency, ACTH deficiency, and hypogonadotropic hypogonadism over time.
- Successfully managed with levothyroxine, hydrocortisone, growth hormone and estradiol therapy.
- Illustrates the progressive, evolving nature of pituitary deficiencies in SOD and the importance of ongoing endocrine surveillance and multidisciplinary care.
- Patient now thriving at age 12, demonstrating resilience and strong engagement in her care.
Contact us
Division of Endocrinology and Diabetes