Rohhad syndrom

ROHHAD Dr.Yassin Alsaleh

Case scenario 1

• 2 years old boy case of :• Microcephaly, mental retardation, SZ disorder,

resolved hypernatremia, sleep apnea ,morbid obesity refered to endocrinlogy as possible case of ROHHAD syndrome.

• Wt:>97th BMI:>97th Ht:10-25th • On oxygen, No goitre , no purple straie.• ACTH , cortisol: WNL. TSH:8.5 Ft4:13

• 9 year old girl case of ROHHADNET with :• Rapid onset of obesity, hypoventilation on

biPAP, adipsic hypernatremia, hypothyrodisim, S/P removal of ganglioneuroma.

Case scenario 2

introduction

• In 1965, Dr. Fishman was the first to describe a constellation of symptoms which he termed Late Onset Central Hypoventilation Syndrome with Hypothalamic Dysfunction (LO-CHS/ HD).

• In 2007, Dr. Diego Ize-Ludlow renamed the disease using the acronym ROHHAD.

• Rapid-Onset.• Obesity.• Hypoventilation.• Hypothalamic.• Autonomic Dysregulation.

ROHH

AD

ROHHAD & ROHHADNET

• Neural tumor syndromeNET

• ROHHAD syndrome is a heterogeneous medical condition .

• Despite increased recognition of the disorder, its incidence is rare with fewer than 100 reported cases in the literature.

• The etiology of this syndrome is still unknown.

introduction

introduction

• life-threatening medical condition with death occurring around the average chronological age of 10.

• ROHHAD syndrome shares many clinical similarities with congenital central alveolar hypoventilation syndrome or Ondine’s curse.

GENETICS• no specific genetic marker has been

implicated . • Nevertheless, familial cases have been

reported, suggesting that it may be a monogenic condition.

• The PHOX2B mutations implicated in CCHS are absent in children with ROHHAD.

• The most common presenting symptom of ROHHAD syndrome is hyperphagia and obesity secondary to hypothalamic dysfunction.

• The typical age of onset is between 2 and 4 years.

Clinical presentation

sudden rapid weight gain and concomitant growth failure (median age at onset: 3 years)

Hypothalmic and autonomic dysregulation (median age at onset: 3.6 years)

behavior and alveolar hypoventilation (median age at onset: 6.2 years).

• Hyperphagia• Obesity.• alveolar hypoventilation• altered respiratory control or thermal or other

hypothalamic dysregulations,• neurobehavioral disorders• tumors of neural crest origin

Clinical presentation

Clinical presentaion ENDOCRINE• Growth failure GH deficiency or unresponsiveness.• excessive secretion of ACTH, hypercortisolism• glucocorticoid deficiency.• hypogonadotropic hypogonadism.• Hyperprolactinemia.• Hypernatremia. Adipsic or Diabetes insipidus.• hypogonadism • precocious puberty,• central hypothyroidism and

Hyperthyrotropinemia.

% manifestation

100 % Rapid-onset obesity

60 % Failed growth hormone stimulation test

53% Hyperphagia

53% Polydipsia

46-100% Hypernatremia 46% Hyperprolactinemia

30% Hypothyroidism

26% Adrenal insufficiency 26% Polyuria 20% Short stature 13% Delayed puberty

13% Hyponatremia

13% Low IGF-1 and IGFBP-3 13% Precocious puberty 13% Premature adrenarche

% manifestation

13% Transient diabetes insipidus

13% Transient SIADH

6% Hypogonadotropic hypogonadism

6% Irregular menses

% manifestation

100% Alveolar hypoventilation

60% Cardiorespiratory arrest

53% Obstructive sleep apnea

obesity• rapid-onset obesity is initial manifestation of

ROHHAD (20–40 lb over 6 –12months). • Almost simultaneously, height velocity will

decrease.• This lead to increase in BMI.• By 6 yr of age, all children had massive obesity.• marked adipomastia ,chubby face and slight

buffalo neck.

ROHHAD VS EXOGENOUS OBESITYROHHAD EXOGENOUS OBESITY

increased increased Sleep apnea

increased increased GH unresponsiveness

High High TSH levels

decreased increased height velocity

low high IGF-I

present absent Autonomic dysfunction

present absent Alveolar hypoventilation

present absent tumors of the sympathetic nervous system

Neural crest tumors• Approximately 40% of the patients may

develop neural crest tumors (ganglioneuro-blastomas, ganglioneuromas,

• usually orginated in the posterior mediastinum or adrenal gland.

• Neural crest tumors are composed of ganglion cells (some of which may be immature) and mature Schwann cells (mature stroma)

• Calcification in CT is common.

RESPIRATORY• Respiratory signs and symptoms may include

obstructive sleep apnea and central hypoventilation,

• which may result in hypoxemia, hypercarbia, cyanosis, or even cardiorespiratory arrest with sudden death.

• median onset age 6 years• ventilatory support is a mainstay of care

Autonomic dysregulation• The most common was thermal dysregulation,

manifest as episodes of hyperthermia or hypothermia .

• pupillary dysfunction and Strabismus.• Gastrointestinal dysmotility with constipation

and chronic diarrhea.

Developmental and neurobehavioral disorders

• mild mental retardation. • developmental regression• obsessive-compulsive disorder.• personality changes, irritability, and physical aggression.• severe avoidance behaviors.• Anxiety .• sleep symptoms. insomnia, and nighttime.• psychosis. • seizures.

Cardiac

• irregular heart rate,• profound bradycardia that required a cardiac

pacemaker• Cardiomyopathy.• heart failure.

diagnostic criteria• 1. rapid onset obesity after a 2 year period of normal

development both in terms of height and weight.• 2. hypothalamic-pituitary endocrine dysfunctions

(hypercortisolism, slow growth, low IGFI, hyperprolactinemia, severe hypernatremia without diabetes insipidus);

• 3. hypothalamic autonomic dysregulation (thermal dysregulation, cold hands and feet, excessive sweating, etc).

• 4. alveolar hypoventilation (obstructive sleep apnea and 2 episodes of respiratory arrest post minimal sedation).

Other DDx• Prader-Willi syndrome.• Bardet-Biedl syndrome.• leptin receptor deficiency.• Cushing’s syndrome.• GH deficiency

MANAGEMENT• Currently there are no definitive tests or

treatments for ROHHAD. • serial pulmonary studies at 3- to 6-month

intervals.• screening for tumors of neural crest origin

every 12 to 18 months.• multi-disciplinary approach is needed in any

potential case of ROHHADNET syndrome.